Substituted pyrrolidin-3-yl-alkyl-piperidines

ABSTRACT

The present invention relates to substituted pyrrolidinyl-3-yl-alkyl-piperidines, their stereoisomers, and pharmaceutically acceptable salts thereof and processes for preparation of the same. The compounds of the present invention are useful in their pharmacological activities such as tachykinin antagonism, especially substance P and neurokinin A antagonism, and the like. Compounds having the property of tachykinin antagonism are indicated for conditions associated with neurogenic inflammation and other diseases described herein.

This application is a Divisional of application Ser. No.08/332,027,filed Oct. 31, 1994, which is a Continuation-in-Part ofapplication Ser. No. 08/225,371, filed Apr. 19, 1994, now abandonded;which is a Continuation-in-Part of application Ser. No. 08/058,606,filed May 6, 1993, now abandoned, and a divisional of Ser. No.08/218,483, filed Mar. 28, 1994, now abandoned.

The present invention relates to substitutedpyrrolidin-3-yl-alkyl-piperidines, isomers, and pharmaceuticallyacceptable salts thereof (herein also referred to as compounds orcompounds of formula (1)) and processes for preparation of the same. Itis an object of the present invention, therefore, to provide new anduseful compounds and pharmaceutically acceptable salts thereof, andprocesses for their preparation.

The compounds of the present invention are useful in theirpharmacological activities such as tachykinin antagonism, especiallysubstance P and neurokinin A antagonism, and the like. Antagonism oftachykinin responses can be elicited through blocking of tachykininreceptors. Three general classes of tachykinin receptors have beendefined by their binding preference to substance P (neurokinin 1receptors (NK₁)), neurokinin A (neurokinin 2 receptors (NK₂)), andneurokinin B (neurokinin 3 receptors (NK₃)). One object of the presentinvention is to provide new and useful antagonists of tachykinins,especially substance P and neurokinin A (NKA). Similarly, antagonism ofneurokinin B (NKB) activities may be important. A particular object ofthe present invention are those compounds that exhibit both NK₁ and NK₂receptor antagonism.

Compounds having the property of tachykinin antagonism are indicated forconditions associated with neurogenic inflammation. Neuropeptides,including the tachykinins substance P and neurokinin A, are releasedfrom capsaicin-sensitive sensory C-fiber neurons. These peptides producelocal effects which may be tissue specific including vasodilation,microvascular leakage, mucus secretion, inflammatory cell recruitmentand priming, smooth muscle contraction and neuronal modulation.Generally, antagonism of the effects of substance P on its preferredreceptor, i.e. NK₁, will not prevent the effects of NKA on its preferredreceptor, i.e. NK₂. Therefore, the potential benefits of having anantagonist at both NK₁ and NK₂ receptors would be to reduce or preventclinical manifestations of a disease which are mediated through bothreceptors.

A further object of the present invention is to provide compounds, orpharmaceutically acceptable salts thereof, for the treatment andprevention of various diseases in a patient in need thereof. Because thecompounds of the present invention are tachykinin antagonists, they arepotentially useful in the treatment of conditions associated withneurogenic inflammation, including asthma, allergies, bronchitis,rhinitis, Crohn's disease, ulcerative colitis, rheumatoid arthritis,osteoarthritis, migraine, cystitis and hypersensitivity reactions.Tachykinin antagonism may also be appropriate therapy for the treatmentof pain, peripheral neuropathy, cough, emesis, post-herpetic neuralgia,adverse immunological reactions, blood flow disorders due tovasodilation, ophthalmic diseases, such as conjuctivitis and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria andthe like. Various central nervous system disorders including anxiety,depression, psychosis, schizophrenia and dementia may also be amenableto treatment with tachykinin antagonists.

Asthma is a particular condition which may be treated with tachykininantagonists. In experimental studies, sensory neuropeptides, especiallytachykinins such as substance P and neurokinin A, can bring about manyof the pathophysiological features of asthma. Neurokinin A producescontraction of airway smooth muscle and increases airway responsivenessto other bronchoconstrictive stimuli. Although also contributing tobronchoconstriction in some species, substance P is more potent in itsability to cause mucus secretion, microvascular leakage andvasodilation. Both tachykinins, substance P and neurokinin A, have beenimplicated in modulation of immune cells including mast cells, Tlymphocytes, macrophages, eosinophils and neutrophils. The effectivenessof the combined NK₁ +NK₂ receptor antagonist, FK 224, has beendemonstrated in asthmatic patients undergoing bradykinin-inducedbronchoconstriction by Ichinose et al. (Lancet (1992) Vol. 340:1248-1251).

The compounds of the present invention are novel. The compounds of thepresent invention act as tachykinin antagonists and are thus potentiallyuseful in the treatment of a number of diseases and conditions asdescribed herein. A further object of the present invention is toprovide a use for compounds, stereoisomers, or pharmaceuticallyacceptable salts thereof, for the treatment or prevention of conditionsand diseases in a patient in need thereof.

LIST OF FIGURES

Reaction Scheme A

Reaction Scheme B

Reaction Scheme C

Reaction Scheme D

Reaction Scheme E

Reaction Scheme E.1

Reaction Scheme F

Reaction Scheme G

Reaction Scheme H

Reaction Scheme I

Reaction Scheme J

Reaction Scheme K

Reaction Scheme K.1

Reaction Scheme L

Reaction Scheme M

FIG. 1a--PI TURNOVER IN UC11 CELLS

FIG. 1b--PI TURNOVER IN SKLKB82#3 CELLS

FIG. 2--INHIBITION OF SP-INDUCED PPE BY EXAMPLE 3

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (1), theirstereoisomers, their N-oxides, and their pharmaceutically acceptablesalts, and processes for preparing the same: ##STR1## wherein G₁ is--CH₂ -- or --C(O)--;

G₂ is --CH₂ -- or --C(O)--;

m is 2 or 3;

n is 0 or 1;

Ar₁ is a radical chosen from the group: ##STR2## wherein R₁ is from 1 to3 substituents each independently chosen from the group consisting ofhydrogen, halogen, hydroxy, CF₃, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy;

R₂ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy;

Ar₂ is a radical chosen from the group ##STR3## wherein R₃ is from 1 to3 substituents each independently chosen from the group consisting ofhydrogen, halogen, C₁ -C₆ alkoxy, hydroxy, --O--C(O)O--CH₂ --CH₃,--OC(O)CH₃, --CF₂ H, --(CH₂)_(q) NR₆ R₇, and --(CH₂)_(q) NR₈ R₉ whereinq is 2 or 3, R₆ is C₁ -C₆ alkyl, R₇ is C₁ -C₆ alkyl, R₈ and R₉ takentogether with the bonded nitrogen form a morpholine ring, piperidinering, 4-methylpiperazine ring, or pyrrolidine ring;

R₄ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy;

Y₁ when selected individually is --C(O)NHR₅, --C(O)NR₆ R₇, or --C(O)NR₈R₉

wherein

R₅ is chosen from the group consisting of hydrogen, C₁ -C₆ alkyl,3-hydroxy-2-butyryl-C₁ -C₆ alkyl ester, 2-glutaryl-C₁ -C₆ alkyl ester,--(CH₂)_(q) NR₆ R₇, and --(C₂)_(q) NR₈ R₉ ;

q is 2 or 3;

R₆ is C₁ -C₆ alkyl;

R₇ is C₁ -C₆ alkyl;

R₈ and R₉ taken together with the bonded nitrogen form a morpholinering, piperidine ring, 4-methylpiperazine ring, or pyrrolidine ring;

Y₂ when selected individually is a radical chosen from the group##STR4## wherein R₁₀ is from 1 to 3 substituents each independentlychosen from the group consisting of hydrogen, halogen, CF₃, C₁ -C₆alkyl, and C₁ -C₆ alkoxy;

R₁₁ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; or

Y₁ and Y₂ together with their attached carbon form a spirocyclic ringchosen from the group ##STR5## wherein the attached carbon is C_(a) ;

R₁₂ is from 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, halogen, CF₃, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy;

R₁₃ is hydrogen, C₁ -C₆ alkyl, or benzyl;

or stereoisomers, or an N-oxide, or a pharmaceutically acceptable saltthereof.

The present invention also provides a method of using the compounds offormula (1) therapeutically in a patient in need thereof, comprisingadministering a therapeutically effective amount of a compound offormula (1).

As is appreciated by one of ordinary skill in the art the compounds ofthe formula (1) may exist as stereoisomers depending on the nature ofthe substituents present. Any reference in this application to one ofthe compounds of the formula (1) is meant to encompass either specificstereoisomers or a mixture of stereoisomers. Where indicated, thecompounds follow the designation of (+)- and (-)- for thestereochemistry of compounds represented by formula (1). It is alsounderstood that the use of the term compounds of the formula (1) and thepreferred embodiment thereof is also inclusive of all its stereoisomers,radicals, salts, and pharmaceutical formulations and compositionsthereof. It is specifically recognized that in the substituted2-(pyrrolidinyl-3-yl)alkyl-piperidines the three position of thepyrrolidine is asymmetric, and may be in the (+)- or (-)- configuration,or may be a mixture thereof. The specific stereoisomers can be preparedby stereospecific synthesis or can be separated and recovered bytechniques known in the art, such as chromatography on chiral stationaryphases, enzymatic resolution, or fractional recrystallization ofaddition salts formed by reagents used for that purpose, as described in"Enantiomers, Racemates, and Resolutions", J. Jacques, A. Collet, and S.H. Wilen, Wiley (1981).

As used in this application:

a) the term "halogen" refers to a fluorine atom, chlorine atom, bromineatom, or iodine atom;

b) the term "C₁ -C₆ alkyl" refer to a branched or straight chained alkylradical containing from 1 to 4 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, cyclopentyl,hexyl, cyclohexyl, etc;

c) the term "C₁ -C₆ alkoxy" refer to a straight or branched alkoxy groupcontaining from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc;

d) the designations --C(O)-- and --CO-- refer to a carbonyl group of theformula: ##STR6## e) the designation "" refers to a bond for which thestereochemistry is not designated;

f) the designations --CO₂ R and --C(O)OR refer to a group of theformula: ##STR7## g) the designation --C(O)NRR refer to a group of theformula: ##STR8## h) as used in the examples and preparations, thefollowing terms have the meanings indicated: "g" refers to grams, "mg"refers to milligrams, "mmol" refers to millimoles, "mL" refers tomilliliters, "cm" refers to centimeters, "L" refers to liters, "° C."refers to degrees Celsius, "R_(f) " refers to retention factor, "mp"refers to melting point, "dec" refers to decomposition, "[α]_(D) ²⁰ "refers to specific rotation of the D line of sodium at 20° C. obtainedin a 1 decimeter cell, "c" refers to concentration in g/mL, "TFA" refersto trifluoroacetic acid, "THF" refers to tetrahydrofuran, "DMF" refersto dimethylformamide, "M" refers to molar, "μL" refers to microliters,"HPLC" refers to high performance liquid chromatography, "eq." refers toequivalents; h refers to hours; "N" refers to normal, "X" refers totimes, "NaHMDS" refers to sodium hexamethyldisilazide or sodiumbis-(trimethylsilyl)amide, "EBA" refers to ethyl bromoacetate, "LiAlH₄ "refers to lithium aluminum hydride, "NMM" refers to 4-methylmorpholine,"aryl₁ " refers to Ar₁, "aryl₂ " refers to Ar₂, "Boc" or t-BOC" refersto t-butyloxycarbonyl; "EDC" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; "HOBT" or "HOBt" refersto 1-hydroxybenzotriazole hydrate, "R_(t) " refers to retention time,"K₂ CO₃ " refers to potassium carbonate, "Na₂ SO₄ " refers to sodiumsulfate, "MgSO₄ " refers to magnesium sulfate, "H₂ O" refers to water,"SOCl₂ " refers to thionyl chloride, "NaOH" refers to sodium hydroxide,"CH₃ CN" refers to acetonitrile, "KOH" refers to potassium hydroxide;

i) the designation ##STR9## refers to a phenyl or substituted phenyl andit is understood that the radical is attached at the 1-position and thesubstituent or substituents represented by R can be attached in any ofthe 2, 3, 4, 5, or 6 positions;

j) the designation ##STR10## refers to a pyridine, substituted pyridine,pyridinyl, or substituted pyridinyl and it is understood that theradical can be attached at the either the 2-position, the 3-position, orthe 4-position, it is further understood that when the radical isattached at the 2-position the substituent or substituents representedby R can be attached in any of the 3, 4, 5, or 6, positions, that whenthe radical is attached at the 3-position the substituent orsubstituents represented by R can be attached in any of the 2, 4, 5, or6 positions, and that when the radical is attached at the 4-position thesubstituent or substituents represented by R can be attached in any ofthe 2, 3, 5, or 6 positions;

k) the designation ##STR11## refers to a thienyl, thiophene, orthiophenyl and it is understood that the radical is attached at the 2-or the 3-positions;

l) the designation ##STR12## refers to a benzyl or substituted benzyland it is understood that the substituent or substituents represented byR can be attached in any of the 2, 3, 4, 5, or 6 positions;

m) the designation ##STR13## refers to a naphthyl, substituted naphthyl,naphthalenyl, substituted naphthalenyl and it is understood that theradical can be attached at the either the 1-position or the 2-position,it is further understood that when the radical is attached at the1-position the substituent or substituents represented by R can beattached in any of the 2, 3, 4, 5, 6, 7, or 8 positions and that whenthe radical is attached at the 2-position the substituent orsubstituents represented by R can be attached in any of the 1, 3, 4, 5,6, 7, or 8 positions;

n) the term "pharmaceutically acceptable salts thereof refers to eitheran acid addition salt or a basic addition salt.

o) the term "enantiomeric excess" or "ee" refers to the percent by whichone enantiomer, E1, is in excess in a mixture of the two enantiomers, E1plus E2, such that; ##EQU1## The term (+)- refers to the plusenantiomer, (-)- refers to the minus enantiomer.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by formula (1) or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulphuric, and phosphoric acid andacid metal salts such as sodium monohydrogen orthophosphate, andpotassium hydrogen sulfate. Illustrative organic acids which formsuitable salts include the mono-, di-, and tricarboxylic acids.Illustrative of such acids are for example, acetic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic,cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, andsulfonic acids such as methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are soluble in water and various hydrophilic organicsolvents, and which in comparison to their free base forms, generallydemonstrate higher melting points.

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by formula (1) or any of itsintermediates. Illustrative bases which form suitable salts includealkali metal or alkaline-earth metal hydroxides such as sodium,potassium, calcium, magnesium, or barium hydroxides; ammonia, andaliphatic, alicyolic, or aromatic organic amines such as methylamine,dimethylamine, trimethylamine, and picoline. Either the mono- ordi-basic salts can be formed with those compounds.

p) the term "N-oxide" refers to the situation where the piperidinenitrogen is additionally bonded to an oxygen atom: ##STR14## Preferredembodiments of formula (1) are given below: 1) When Y₁ and Y₂ are chosenindependently, a preferred embodiment is where Y₁ is chosen to be--C(O)NHR₅ ;

2) When Y₁ and Y₂ are chosen independently a preferred embodiment iswhere Y₂ is chosen to be phenyl or substituted phenyl;

3) A preferred embodiment is when m is 2;

4) A preferred embodiment is when n is 0;

5) A preferred embodiment is when G₁ is --CH₂ -- and G₂ is --C(O)--;

6) A preferred embodiment is when G₁ is --C(O)-- and G₂ is --CH₂ --.

It is understood that further preferred embodiments of formula (1) canbe selected by requiring one or more of the preferred embodiments above.

Nomenclature of the titled compounds of the invention were generated inpart with the AUTONOM program, Version 1.0, of the Beilstein Institute,distributed by Springer-Verlag, Heidelberg (Copyright 1990, 1991) whichare illustrated in Table 1 with their AUTONOM generated name andcorresponding example number for several of the examples.

                  TABLE 1                                                         ______________________________________                                        Example #                                                                            General Nomenclature                                                   ______________________________________                                        9      8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-                               benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-                       spiro[4.5]decane-4-one                                                 3      1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-                            benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                5      1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-                               benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                4      1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-                                phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl]-4-phenyl-                             piperidine-4-carboxylic acid amide                                     13     1-[2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-                          pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-                                carboxylic acid amide                                                  2      1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-                               benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                6      2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-                        yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-                            pentanedioic acid dimethyl ester                                       11     1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-                                 pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-                                carboxylic acid amide                                                  1      1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-                         yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid                              amide                                                                  10     8-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-                         yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-                         one                                                                    7      2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-                                  pyrrolidin-3-yl]-ethyl-4-phenyl-piperidine-4-                                 carboxyl)-amino]-3-hydroxy butyric acid methyl ester                   12     1-[2-(1-benzoyl-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl)-                     ethyl]-4-phenyl-piperidine-4-carboxylic acid amide                     8      1-[2-(1-benzoyl-3-napthalen-2-yl-pyrrolidin-3-yl)-                            ethyl]-4-phenyl-piperidine-4-carboxylic acid amide                     20     (+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-                                   trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-                         piperidine-4-carboxylic acid amide                                     21     (-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-                        benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                23     1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-                           benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                24     1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-                                     (trifluoromethyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-                           piperidine-4-carboxylic acid amide                                     25     1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-                               benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid amide                                                26     1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-                            benzoyl)-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-                         4-carboxylic acid (2-dimethylamino-ethyl)-amide                        27     1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-                          pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-                                carboxylic acid amide                                                  22     1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-                                  pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-                                carboxylic acid amide                                                  ______________________________________                                    

Illustrative Examples of compounds encompassed by the present inventioninclude:

8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-one;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-pentanedioicacid dimethyl ester;

1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

8-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-one;

2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxyl)-amino]-3-hydroxybutyric acid methyl ester;

1-[1-benzyl-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-(1-benzoyl-3-napthalen-2-yl-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-dimethylamino-ethyl)-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(benzo[1,3]-dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(naphth-2-yl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-4-yl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-2-yl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-benzyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidlne-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;

8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one;

8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;

3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;

8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;

1-[2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(4-hydroxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(thiophen-2-yl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dibromo-4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-methyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methoxy-phenyl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-difuloromethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(2-diethylamino-ethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide;

1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide.

Examples of compounds of the (+) isomer encompassed by the presentinvention include:

(+)8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-oneand the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-pentanedioicacid dimethyl ester and the hydrochloride salt thereof;

(+)-1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-8-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-oneand the hydrochloride salt thereof;

(+)-2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxyl)-amino]-3-hydroxybutyric acid methyl ester and the hydrochloride salt thereof;

(+)-1-[1-benzyl-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-(1-benzoyl-3-napthalen-2-yl-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-dimethylamino-ethyl)-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(benzo[1,3]-dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(naphth-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-4-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-benzyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(+)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-oneand the hydrochloride salt thereof;

(+)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(+)-3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(+)-3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dioneand the hydrochloride salt thereof;

(+)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dioneand the hydrochloride salt thereof;

(+)-1-[2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(4-hydroxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(thiophen-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dibromo-4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-methyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-yl[-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3yl[-ethyl]-4(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4,5-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(methyl-phenyl)-piperdine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-difuloromethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(2-diethylamino-ethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide and the hydrochloride salt thereof;

(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof.

Examples of compounds of the (-) isomer encompassed by the presentinvention include:

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-oneand the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-pentanedioicacid dimethyl ester and the hydrochloride salt thereof;

(-)-1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-oneand the hydrochloride salt thereof;

(-)-2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxyl)-amino]-3-hydroxybutyric acid methyl ester and the hydrochloride salt thereof;

(-)-1-[1-benzyl-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-(1-benzoyl-3-napthalen-2-yl-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-dimethylamino-ethyl)-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(benzo[1,3]-dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(naphth-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-4-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-benzyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-oneand the hydrochloride salt thereof;

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(-)-3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand the hydrochloride salt thereof;

(-)-3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dioneand the hydrochloride salt thereof;

(-)-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dioneand the hydrochloride salt thereof;

(-)-1-[2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(4-hydroxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl ]-4-phenyl-piperidine-4-carboxylic acid amide and thehydrochloride salt thereof;

(-)-1-[2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(thiophen-2-yl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dibromo-4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1(3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoyl)-pyrrolidin3yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-methyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methoxy-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-difuloromethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(2-diethylamino-ethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide and the hydrochloride salt thereof;

(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide and the hydrochloride salt thereof.

REACTION SCHEMES

Compounds of formula (1) and intermediates thereof can be prepared asdescribed in the Reaction Schemes A through M below. All thesubstituents, unless otherwise indicated, are previously defined. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Reaction Scheme A

Reaction Scheme A may be used to synthesize substituted1-aralkyl-3-aryl-3-(2-hydroxyethyl)-5-oxo-pyrrolidine as shown informula 5a (see scheme A on next page). The substituents of formula 5a,1-aralkyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines, are defined such thatAr₁ and Ar₂ are as desired in the final product.

In reaction Scheme A, Step A1, alkylation of the aryl-acetonitrile maybe accomplished with 2-(2-bromo-ethoxy)-tetrahydro-pyran to form the2-aryl-4-(tetrahydro-pyran-2-yloxy)-butyronitrile which is then followedby a second alkylation with ethyl bromoacetate (step A2) to form the3-cyano-3-aryl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acid ethyl ester(compound 2).

The 3-cyano-3-aryl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acid ethylester is able to be converted to the corresponding lactam by reduction,as is illustrated by treatment with hydrogen and Raney nickel (step A3)to form the corresponding4-aryl-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one (compound3).

The selected aralkyl group having the desired substituents previouslydefined for formula 5a, may be added to pyrrolidine ring nitrogen byalkylation with an aralkyl halide, such as benzyl bromide, (step A4) toform ##STR15## the corresponding1-aralkyl-4-aryl-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one.

The 5(a) intermediate corresponding to the1-aralkyl-4-aryl-4-(2-hydroxyethyl)-pyrrolidin-2-one may be obtained byremoval of the tetrahydropyran group by treatment of compound 4 with asuitable acid, such as p-toluenesulfonic acid in methanol.

Reaction Scheme B

Reaction Scheme B may be used to synthesize intermediate compoundswherein the structure is a substituted1-aroyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidine, as shown in formula 5b,or a substituted 1-arylacetyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidine.##STR16## The compounds of formula 5b,1-aroyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines and1-phenylacetyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines are defined suchAr₁ and Ar₂ are as desired in the final product.

In reaction Scheme B, Step B1, the aryl-acetonitrile is treated with abase, for example, sodium bis (trimethylsily)amide), followed byaddition of ethyl bromoacetate to produce the3-cyano-3-aryl-pentanedioic diethyl ester (compound 7).

The 3-cyano group of the 3-cyano-3-aryl-pentanedioic diethyl ester maythen subsequently be reduced with an appropriate reducing reagent (stepB2), for example Raney nickel and hydrogen or with cobalt (II) chlorideand sodium borohydride to give the corresponding3-aryl-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (compound 8).

The 3-aryl-5-oxo-pyrrolidin-3-yl-acetic acid ethyl ester (compound 8)may subsequently be used in Scheme C or the 5-oxo-pyrrolidine ring maybe reduced (step B3) with an appropriate reducing reagent, such aslithium aluminum hydride or aluminum hydride, to form the corresponding3-aryl-3-(2-hydroxyethyl)-pyrrolidine (compound 9).

The pyrrolidine of compound 9 may subsequently be aroylated with anappropriately substituted benzoyl chloride in the presence of base suchas 4-methylmorpholine to form the corresponding1-aroyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidine (Compound 5b) orsubstituted with an approprately substituted with a substitutedarylacetyl chloride or aroyl chloride to form the corresponding1-arylacetyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidine or1-aroyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidine.

Reaction Scheme C

Reaction Scheme C is an alternative route which may be used tosynthesize intermediate compounds wherein the structure is a substituted1-aralkyl-3-aryl-3-(2-hydroxyethyl)-5-oxo-pyrrolidine as shown informula 5a. ##STR17## The substituents of formula 5a,1-aralkyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines, have been previousdefined wherein Ar₁ and Ar₂ are as desired in the final product.

A selected group from aryl may be added to the pyrrolidine ring of the(3-aryl-5-oxo-pyrrolidin-3-yl)-acetic acid ethyl ester (compound 8) byalkylation (step C1) of the nitrogen of pyrrolidine with an aralkylhalide, such as benzyl bromide, for example, to form the corresponding1-aralkyl-3-aryl-5-oxo-pyrrolidin-3-yl-acetic acid ethyl ester (compound10).

Conversion of the ethyl ester of compound 10 to the corresponding acidof compound 11 may be accomplished by base hydrolysis, for examplelithium hydroxide in methanol, to form the1-aralkyl-3-aryl-5-oxo-pyrrolidin-3-yl-acetic acid (compound 11).

The acetic acid of compound 11 is subsequently able to be reduced, forexample, via the corresponding mixed anhydride in the presence of sodiumborohydride to form the1-aralkyl-4-aryl-4-(2-hydroxyethyl)-pyrrolidin-2-ones shown (compound5c).

Reaction Scheme D

Reaction Scheme D may be used to synthesize the aryl substituted2-(pyrrolidin-3-yl)-ethyl-piperidines of the invention. ##STR18## SchemeD is a general type procedure for condensation of substitutedpiperidines with substituted1-aralkyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines, substituted1-aroyl-3-arylacetyl-3-(2-hydroxyethyl)-pyrrolidine, or substituted1-aroyl-3-aryl-3-(hydroxyethyl)-pyrrolidines previously discussed inSchemes A (Compound 5a), B (Compound 5b), or C (Compound 5c). Thecompounds of formula 15 are derived from the starting compoundsdescribed for Compounds 5a, 5b, and 5c, wherein the Ar₁ and At2 is asdesired in the final product.

Conversion of 1-aralkyl-3-aryl-3-(2-hydroxyethyl)-pyrrodidines,1-arylacetyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines, or1-aroyl-3-aryl-3-(2-hydroxyethyl)-pyrrolidines of intermediates 5a, 5b,or 5c may be accomplished by converting the 2-hydroxyethyl group to thecorresponding mesylate by allowing 5a or 5b to react withmethanesulfonyl chloride (step D1) and then allowing the mesylatederivative to react with a piperidine derivative to form the titled arylsubstituted 2-(pyrrolidin-3-yl)-ethyl-piperidines of formula 15. It isrealized that although the 4-phenyl-piperidine-4-carboxylic acid amideis shown as the substituted piperidine it may be replaced by a number ofother piperidines or substituted piperidines. For instance, thepiperidine derivatives may be condensed with the1-aroyl-3-aryl-3-(2-hydroxy-ethyl)-pyrrolidine by refluxing thecompounds in THF/water with a weak base, such as sodium bicarbonate orpotassium carbonate. Suitable piperidine derivatives for condensationinclude, but are not limited to 4-phenyl-piperidine-4-carboxylic acidamide (4-phenyl isonipecotamide),1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, and the like.

The piperidine derivative can be further reacted following condensationwith the mesylate. For example, one can use the4-phenyl-piperidine-4-carboxylic acid methyl ester in the condensationwith the mesylate derived from a 3-hydroxy-ethyl-pyrrolidine. Aftercondensation of the piperidine derivative with the mesylate the4-carboxylic acid ester protecting group may be removed to afford anintermediate acid derivative and further reacted to form the appropriatealkyl amides.

Reaction Scheme E

Reaction Scheme E is a general scheme for preparing the compounds offormula (1). ##STR19##

In Reaction Scheme E, step 1, the hydroxy group of an appropriate3-(ω-hydroxyalkyl)pyrrolidine compound of formula 16 is converted to anappropriate leaving group. An appropriate 3-(ω-hydroxyalkyl)pyrrolidinecompound of formula 16 is one in which m, n, G₁, G₂, Ar₁ and Ar₂ are asdesired in the final product of formula (1) or can be one in which Ar₁gives rise after deprotection to a group Ar₁ as desired in the finalproduct of formula (1). An appropriate leaving group, L₁, is one whichcan be displaced by a piperidine of formula 18 to give a compound offormula (1). Appropriate leaving groups, L₁, include but are not limitedto chloro, bromo, iodo, mesylate, tosylate, benzenesulfonate,trifluoromethanesulfonate, and the like. The conversion of hydroxygroups to leaving groups such as chloro, bromo, iodo, mesylate,tosylate, benzenesulfonate, and trifluoromethanesulfonate is well knownand appreciated in the art.

For example, compounds in which L₁ is bromo are formed by contacting anappropriate 3-(ω-hydroxyalkyl)pyrrolidine compound of formula 16 with1.0 to 1.5 molar equivalents of carbon tetrabromide and 1.0 to 1.75molar equivalents triphenylphosphine. (P. J. Kocienski et al. JOC 42,353-355 (1977)). The reaction is carried out by combining the3-(ω-hydroxyalkyl)pyrrolidine compound of formula 16 with carbontetrabromide in a suitable solvent, such as dichloromethane orchloroform and then adding a solution of triphenylphosphine in asuitable solvent, such as dichloromethane or chloroform. Generally thereaction is carried out at temperatures of from -10° C. to ambienttemperature. Generally, the reactions require from 5 minutes to 24hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

Compounds in which L₁ , is bromo are also formed by contacting anappropriate 3-(ω-hydroxyalkyl)pyrrolidine compound of formula 16 with aslight molar excess of triphenylphosphine dibromide. (R. F Borch et al.JACS 99, 1612-1619 (1977)). The reaction may be carried out bycontacting an appropriate 3-(ω-hydroxyalkyl)pyrrolidine compound offormula 16 with preformed triphenylphosphine dibromide. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran and diethylether. The reaction is carried out in the presence of a suitable base,such as pyridine. Generally the reaction is carried out at temperaturesof from 0° C. to 50° C. Generally, the reactions require from 5 minutesto 24 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

Alternately, for example, compounds in which L₁ is mesylate are formedby contacting an appropriate 3-(ω-hydroxyalkyl)pyrrolidine compound offormula 16 with a molar excess of methanesulfonyl chloride. The reactionis carried out in a suitable solvent, such as dichloromethane,chloroform, toluene, benzene, or pyridine. The reaction is carried outin the presence of a suitable base, such as triethylamine,diisopropylethyl amine, or pyridine. Generally the reaction is carriedout at temperatures of from -20° C. to 50° C. Generally, the reactionsrequire from 1 hour to 24 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

Compounds of formula 17 in which L₁ is iodo can be prepared fromcompounds of formula 17 in which L₁ is mesylate, chloro, or bromo by anexchange reaction, such as the Finkelstein reaction.

For example, a Compound of formula 17 in which L₁ is mesylate, chloro,or bromo is contacted with from 1.0 to 10.0 molar equivalents of aniodide salt, such as sodium iodide or potassium iodide. The reaction iscarried out in a suitable solvent, such as acetone or butanone.Generally, the reaction is carried out at temperatures of from ambienttemperature to the refluxing temperature of the solvent. Generally, thereactions require from 1 hour to 24 hours. The product can be isolatedand purified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme E, step 2, an appropriate 3-(ω-L₁ -alkyl)pyrrolidinecompound of formula 17 reacts with an appropriate piperidine compound offormula 18 or salt of an appropriate piperidine of formula 18 to give aprotected compound of formula (1) or a compound of formula (1). Anappropriate compound of formula 17 is one in which the leaving group,L₁, is one which can be displaced by a piperidine of formula 18, m, n,G₁, G₂, Ar₁ and Ar₂ are as desired in the final product of formula (1)or can be one in which Ar₁ gives rise after deprotection to a group Ar₁as desired in the final product of formula (1). An appropriatepiperidine of formula 18 or salt of an appropriate piperidine of formula18 is one in which Y₁ and Y₂ are as desired in the final product offormula (1).

For example, an appropriate 3-(ω-L₁ -alkyl)pyrrolidine compound offormula 17 is contacted with an appropriate piperidine compound offormula 18 or salt of an appropriate piperidine of formula 18 to give aprotected compound of formula (1) or a compound of formula (1). Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,tetrahydrofuran/water mixtures, pyridine, acetonitrile, toluene,toluene/water mixtures, or dimethylformamide. The reaction is carriedout in the presence of from 1.0 to 6.0 molar equivalents of a suitablebase, such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, triethylamine, pyridine, ordiisopropylethylamine. When a salt of an appropriate piperidine offormula 18 is used, an additional molar excess of a suitable base isused. The reaction may be facilitated by the addition of a catalyticamount, 0.1 to 0.5 molar equivalents, of an iodide salt, such as sodiumiodide or potassium iodide. The reaction is generally carried out attemperatures of from ambient temperature to the refluxing temperature ofthe solvent. Generally, the reactions require 1 to 72 hours. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme E, optional step 3, a protected compound of formula(1) is deprotected to give a compound of formula (1). A deprotectionreaction, such as the removal of hydroxy protecting groups utilizingsuitable protecting groups such as those described in Protecting Groupsin Organic Synthesis by T. Greene is well known and appreciated in theart.

Alternately, the compounds of formula (1) can be prepared by forming theamide group after the formation of an appropriate carboxylic acidderivative as generally taught below.

In Reaction Scheme E, optional step 4, an appropriate compound offormula 17, as defined above is contacted with an appropriate piperidineester of formula 19 or salt of an appropriate piperidine ester offormula 19. An appropriate piperidine ester of formula 19 or salt of anappropriate piperidine ester of formula 19 is one in which Y₂ is asdesired in the final product of formula (1) and Z is a C₁ -C₄ alkylgroup. This step is carried out as generally taught in Reaction SchemeE, step 2.

In Reaction Scheme E, step 5, an appropriate ester of formula 20 ishydrolyzed to give an acid of formula 21.

For example, an appropriate ester of formula 20 is contacted with asuitable hydrolyzing agent, such as sodium hydroxide, potassiumhydroxide, or lithium hydroxide. The reaction is carried out in asuitable solvent such as water, tetrahydrofuran/water mixtures,methanol, methanol/water mixtures, or ethanol/water mixtures. Thereaction is generally carried out at temperatures of from 0° C. to therefluxing temperature of the solvent. Generally, the reactions require 1to 72 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme E, step 6, an appropriate acid of formula 21undergoes an amidation reaction with an appropriate amine to give acompound of formula (1). An appropriate amine, NH₂ R₅, NHR₆ R₇, or NHR₈R₉, is one which R₅, R₆ and R₇, and R₈ and R₉ are as desired in thefinal compound of formula (1).

An amidation reaction may proceed through the acid of formula 21 or theacid function of a compound of formula 21 may be first converted to anactivated intermediate; such as an anhydride; a mixed anhydride ofsubstituted phosphoric acid, such as dialkylphosphoric acid,diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylicacid, such as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroaceticacid, trifluoroacetic acid, and the like; of aromatic carboxylic acids,such as benzoic acid and the like; an activated ester, such as phenolester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenolester, pentachlorophenol ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester, and thelike; activated amide, such as imidazole, dimethylpyrazole, triazole, ortetrazole; or the intermediate formed in the presence of couplingagents, such as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Activated intermediatesmay be prepared and used directly, or are prepared and isolated beforethe addition of an appropriate amine, NH₂ R₅, NHR₆ R₇, or NHR₈ R₉.Alternately, activated intermediates may be prepared isolated andpurified before the addition of an appropriate amine, NH₂ R₅, NHR₆ R₇,or NHR₆ R₉. The use and formation of activated intermediates is wellknown and appreciated in the art.

For example, an acid compound of formula 21 is contacted with a slightmolar excess of an appropriate amine, NH₂ R₅, NHR₆ R₇, or NHR₈ R₉, or asalt of an appropriate amine and 1-hydroxybenzotriazole hydrate in thepresence of a slight molar excess of a coupling agent, such asdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction is carriedout in the presence of a suitable base, such as diisopropylethyl amine,N-methylmorpholine, or triethylamine. If the salt of an amine is used anadditional equimolar of a suitable base is added. The reaction iscarried out in a suitable solvent, such as dichloromethane orchloroform. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

Alternatively, for example, an acid of formula 21 is contacted with 1.2to 1.7 equivalents of a suitable base, such as N-methylmorpholine, in asuitable solvent, such as tetrahydrofuran. The reaction mixture iscooled to a temperature of between -50° C. and 0° C. with -25° C. to-20° C. being preferred, before the addition of 1.2 to 1.7 equivalentsof isobutyl chloroformate. The reaction is allowed to stir for 30minutes to 24 hours to allow for the formation of the mixed anhydride,an activated intermediate. While maintaining the temperature at between-50° C. and 0° C. an appropriate amine, NH₂ R₅, NHR₆ R₇, or NHR₈ R₉, isadded, if the salt an appropriate amine is used an additional equimolaramount of a suitable base is added. The reaction may, after the additionof amine is complete, be warmed to room temperature. Generally, thereaction requires from 2 to 48 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, chromatography, and recrystallization.

The protected compounds of formula (1) prepared as described in ReactionScheme E, optional step 4, step 5, and step 6 can be deprotected asrequired as described in Reaction Scheme E, optional step 3.

The N-oxide and pharmaceutically acceptable salt of compounds of formula(1) are readily prepared from compounds of formula (1) by methods andtechniques well known and appreciated in the art.

Reaction Scheme E.1

Reaction Scheme E.1 is a general scheme for preparing the compounds offormula (1) in which G₁ is --CH₂ --. ##STR20##

In Reaction Scheme E.1, step 1, the amino group of an appropriate3-aryl-3-(ω-hydroxyethyl)-pyrrolidine of formula 48a is protected togive an appropriate protected 3-aryl-3-(ω-hydroxyethyl)-pyrrolidine offormula 48b. An appropriate 3-aryl-3-(ω-hydroxyethyl)-pyrrolidine offormula 48a is one in which the m and Ar₁ are as desired in the finalproduct of formula (1) or can be one in which Ar₁ gives rise afterdeprotection to a group Ar₁ as desired in the final product of formula(1). Compounds of formula 48a are readily prepared as described inReaction Scheme J for the preparation of compounds of formula 48 or bydeprotection of tetrahydropyran ethers of compounds of formula 44prepared in Reaction Scheme I or compounds of formula 31 prepared inReaction Scheme F.

The selection and use of suitable amino protecting groups such as, t-BOCand those described in Protecting Groups in Organic Synthesis by T.Greene is well known and appreciated in the art.

In Reaction Scheme E.1, step 2, the hydroxy group of an appropriateprotected 3-aryl-3-(ω-hydroxyethyl)-pyrrolidine of formula 48b isconverted to an appropriate leaving group as generally taught inReaction Scheme E, step 1 to give an appropriate protected3-aryl-3-(ω-L₁ -alkyl)pyrrolidine compound of formula 17a.

In Reaction Scheme E.1, step 3, an appropriate protected 3-aryl-3-(ω-L₁-alkyl)pyrrolidine compound of formula 17a reacts with an appropriatepiperidine compound of formula 18 or salt of an appropriate piperidineof formula 18 to give a protected compound of formula (1) as generallytaught in Reaction Scheme E, step 2 to give an appropriate protected3-aryl-3-(ω-piperidino-alkyl)pyrrolidine compound of formula 17b.

In Reaction Scheme E.1, step 4, an appropriate protected3-aryl-3-(ω-piperidino-alkyl)pyrrolidine compound of formula 17b isdeprotected to give an appropriate3-aryl-3-(ω-piperidino-alkyl)pyrrolidine compound of formula 17c or asalt of an appropriate 3-aryl-3-(ω-piperidino-alkyl)pyrrolidine compoundof formula 17c. The removal of suitable amino protecting groups such as,t-BOC and those described in Protecting Groups in Organic Synthesis byT. Greene is well known and appreciated in the art.

In Reaction Scheme E.1, step 5, an appropriate3-aryl-3-(ω-piperidino-alkyl)pyrrolidine compound of formula 17c isalkylated as generally taught in Reaction Scheme I, optional step 2, togive a compound of formula (1) or a protected compound of formula (1) inwhich G₂ is --CH₂ -- or is aroylated as generally taught in ReactionScheme I, optional step 3, to give a compound of formula (1) or aprotected compound of formula (1) in which G₂ is --CH₂ --.

In Reaction Scheme E.1, optional step 6, a protected compound of formula(1) is deprotected to give a compound of formula (1) as generally taughtin Reaction scheme E, optional step 3.

Reaction Scheme F

Reaction Scheme F is a general scheme for preparing intermediates offormula 16 useful for preparing compounds of formula (1). ##STR21##

In Reaction Scheme F, step 1, an appropriate aryl-acetonitrile offormula 23 is alkylated with an appropriate ω-leavinggroup-THP-protected alcohol of formula 22 to give anω-THP-protected-hydroxyalkyl-aryl-acetonitrile of formula 24. Anappropriate aryl-acetonitrile of formula 23 is one in which Ar₁ is asdesired in the final product of formula (1) or gives rise afterdeprotection to an Ar₁ as desired in the final product of formula (1).An appropriate ω-leaving group-THP-protected alcohol of formula 22 inone in which m is 2 or 3 as desired in the final product of formula (1)and the leaving group, L₂, is one which can be displaced by an anionderived from an appropriate aryl-acetonitrile of formula 23. Suitableleaving groups include but are not limited to chloro, bromo, iodo, andmesylate with bromo being preferred.

For example, an appropriate aryl-acetonitrile of formula 23 is contactedwith an equimolar amount of an appropriate ω-leaving group-THP-protectedalcohol of formula 22. The reaction is carried out in the presence of abase, such as sodium hydride, sodium hexamethyldisilazide, potassiumt-butoxide, and lithium diisopropylamide with sodium hydride and sodiumhexamethyldisilazide being preferred. The reaction is carried out in asolvent, such as dimethylformamide or tetrahydrofuran. The reaction isgenerally carried out at temperatures of from -78° C. to 0° C.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme F, step 2, an appropriateω-THP-protected-hydroxyalkyl-aryl-acetonitrile of formula 24 isalkylated with ethyl bromoacetate to give a nitrile ester compound offormula 25.

For example, an appropriateω-THP-protected-hydroxyalkyl-aryl-acetonitrile of formula 24 iscontacted with approximately a molar equivalent of ethyl bromoacetate.The reaction is carried out in the presence a suitable base, such as,sodium hexamethyldisilazide or lithium diisopropylamide. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran. The reactionis generally carried out at temperatures of from -78° C. to 0° C.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme F, step 3, an appropriate nitrile ester compound offormula 25 is reduced and cyclized to give a5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26.

For example, an appropriate nitrile ester compound of formula 25 iscontacted with an appropriate reducing agent, such as sodium borohydridein the presence of cobalt (II) chloride hexahydrate or hydrogen in thepresence of a suitable catalyst, such as Raney nickel. For compounds offormula 25 in which Ar₁ is thienyl, sodium borohydride in the presenceof cobalt (II) chloride hexahydrate is preferred.

When sodium borohydride in the presence of cobalt chloride is used, thereaction is carried out in a suitable solvent, such as methanol, orethanol. The reaction is generally carried out at temperatures of from0° C. to 50° C. Generally, the reactions require 1 to 72 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction with aqueous acid, evaporation, trituration,chromatography, and recrystallization.

When Raney nickel is used, the reaction is carried out in a suitablesolvent containing ammonia, such as ethanol/ammonium hydroxide. Thereaction is generally carried out at temperatures of from ambienttemperature to 50° C. The reaction is carried out at pressures of from15 psi to 120 psi in an apparatus designed for carrying out reactionsunder pressure, such as a Parr hydrogenation apparatus. The product canbe isolated by carefully removing the catalyst by filtration andevaporation. The product can be purified by extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme F, optional step 4, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is alkylated with an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂,to an N-arylaklyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl)pyrrolidine of formula 27. An appropriate alkyl halide, X--CH₂--(CH₂)_(n) ---Ar₂, is one in which X is chloro, bromo, or iodo; n is asdesired in the final product of formula (1), and Ar₂ is as desired informula (1).

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is contacted with from 1 to 5 molar equivalents of an appropriate alkylhalide, X--Ch₂ --(CH₂)_(n) --Ar₂. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, ordimethylformamide. The reaction is carried out in the presence of abase, such as sodium hydride, potassium t-butoxide, or lithiumdiisopropylamide with sodium hydride being preferred. The reaction isgenerally carried out at temperatures of from 0° C. to 50° C. Generally,the reactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme F, optional step 5, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is aroylated with an appropriate aroyl halide, aryl anhydride, or arylmixed anhydride, A-C(O)--(C₂)_(n) --Ar₂, to anN-aroyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 28. An appropriate aroyl halide, aryl anhydride, or aryl mixedanhydride, A-C(O)--(CH₂)_(n) --Ar₂, is one in which A is an activatedleaving group, such as chloro or bromo, an anhydride, or mixedanhydride, n is as desired in the final product of formula (1), and Ar₂is as desired in formula (1).

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is contacted with 1 to 1.5 molar equivalents of an appropriate aroylhalide, aryl anhydride, or aryl mixed anhydride, A-C(O)--(CH₂)_(n)--Ar₂. The reaction is carried out in a suitable solvent, such astetrahydrofuran, N,N-dimethylaniline, or diethyl ether. The reaction iscarried out in the presence of a base, such as sodium hydride,N,N-dimethylaniline, potassium t-butoxide, or lithium diisopropylamidewith sodium hydride being preferred. The reaction is generally carriedout at temperatures of from -20° C. to the reflux temperature of thesolvent. Generally, the reactions require 1 to 24 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme F, step 6, anN-arylaklyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 27 is deprotected to give anN-arylaklyl-5-oxo-3-aryl-3-(ω-hydroxyalkyl) pyrrolidine of formula 16which gives rise to compounds of formula (1) in which G₁ is --C(O)-- andG₂ is --CH₂ -- and m, n, Ar₁, and Ar₂ are as desired in the finalproduct of formula (1) or give rise after deprotection to Ar₁ as desiredin the final product of formula (1).

For example, anN-arylaklyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 27 is treated with a suitable acid, such as p-toluenesulfonicacid. The reaction is carried out in a suitable solvent, such asmethanol or ethanol. The product is isolated by evaporation and purifiedby techniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme F, step 7, anN-aroyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 28 is deprotected, as taught above for Reaction Scheme F, step6, to give an N-aroyl-5-oxo-3-aryl-3-(ω-hydroxyalkyl) pyrrolidine offormula 16 of which gives rise to compounds of formula (1) in which G₁is --C(O)-- and G₂ is --C(O)-- and m, n, Ar₁, and Ar₂ are as desired inthe final product of formula (1) or give rise after deprotection to Ar₁as desired in the final product of formula (1).

In Reaction Scheme F, optional step 8, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is reduced to give a 3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidineof formula 31.

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 26is contacted with a suitable reducing agent, such as lithium aluminumhydride, aluminum hydride, or borane dimethyl sulfide complex. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran.The reaction is generally carried out at temperature of from 0° C. tothe refluxing temperature of the solvent. Generally, the reactionsrequire 1 to 72 hours. The product can be isolated and purified bytechniques well known in the art, such as quenching of borane oraluminum complexes, extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme F, optional step 9, an appropriate3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 31 isalkylated with an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, toan N-arylaklyl-3-aryl-3--(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 33. An appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, isone in which X is chloro or bromo, n is as desired in the final productof formula (1), and Ar₂ is as desired in formula (1).

For example, an appropriate 3-aryl-3-(ω-THP-protected-hydroxyalkyl)pyrrolidine of formula 31 is contacted with from 1.0 to 1.2. molarequivalents of an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂.The reaction is carried out in a suitable solvent, such astetrahydrofuran, dimethyl sulfoxide, acetonitrile,tetrahydrofuran/water, toluene, toluene/water, or dimethylformamide. Thereaction is carried out in the presence of a base, such as sodiumcarbonate, sodium bicarbonate, potassium carbonate, triethylaminediisopropylethylamine, or pyridine. The reaction is generally carriedout at temperatures of from 0° C. to reflux temperature of solvent.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme F, optional step 10, an appropriate3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula 31 isaroylated with an appropriate aroyl halide, aryl anhydride, or arylmixed anhydride, A-C(O)--(CH₂)_(n) --Ar₂, to anN-aroyl-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula32. An appropriate aroyl halide, aryl anhydride, or aryl mixedanhydride, A-C(O)--(CH₂)_(n) --Ar₂, is one in which A is an activatedleaving group, such as chloro or bromo, an anhydride, or mixedanhydride, n is as desired in the final product of formula (1), and Ar₂is as desired in formula (1).

For example, an appropriate 3-aryl-3-(ω-THP-protected-hydroxyalkyl)pyrrolidine of formula 31 is contacted with 1 to 1.5 molar equivalentsof an appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,A-C(O)--(CH₂)_(n) --Ar₂. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, acetonitrile, dimethylformamide, orpyridine. The reaction is carried out in the presence of a base, such assodium carbonate, sodium bicarbonate, triethylamine,diisopropylethylamine, or pyridine. The reaction is generally carriedout at temperatures of from -20° C. to 50° C. Generally, the reactionsrequire 1 to 24 hours. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme F, step 11, anN-arylaklyl-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine offormula 33 is deprotected to give anN-arylaklyl-3-aryl-3-(ω-hydroxyalkyl) pyrrolidine of formula 16 whichgives rise to compounds of formula (1) in which G₁ is --CH₂ --, G₂ is--CH₂ --, m, n, Ar₁, and Ar₂ are as desired in the final product offormula (1) or give rise after deprotection to Ar₁ as desired in thefinal product of formula (1).

For example, an N-arylaklyl-3-aryl-3-(ω-THP-protected-hydroxyalkyl)pyrrolidine of formula 33 is treated with a suitable acid, such asp-toluenesulfonic acid. The reaction is carried out in a suitablesolvent, such as methanol or ethanol. The product is isolated byevaporation and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme F, step 12, anN-aroyl-3-aryl-3-(ω-THP-protected-hydroxyalkyl) pyrrolidine of formula32 is deprotected, as taught above in Reaction Scheme F, step 11, togive an N-aroyl-3-aryl-3-(ω-hydroxyalkyl)pyrrolidine of formula 16 whichgives rise to compounds of formula (1) in which G₁ is --CH₂ --, G₂ is--C(O)--, and m, n, Ar₁, and Ar₂ are as desired in the final product offormula (1) or give rise after deprotection to Ar₁ as desired in thefinal product of formula (1).

Reaction Scheme G

Reaction Scheme G is a general scheme for preparing intermediates givingrise to compounds of formula (1) wherein m is 2. ##STR22##

In Reaction Scheme G, step 1, an appropriate aryl acetonitrile offormula 23 is alkylated twice with ethyl bromoacetate to give a nitrilebis-ester compound of formula 35. An appropriate aryl acetonitrile offormula 23 is one in which Ar₁ is as is desired in the final product offormula (1) or gives rise after deprotection to an Ar₁ as desired in thefinal product of formula (1).

For example, an appropriate aryl acetonitrile of formula 23 is contactedwith 2.0 to 3.0 molar equivalents of ethyl bromoacetate. The reaction iscarried out in the presence of approximately 2.0 to 3.0 molarequivalents of a suitable base, such as sodium hexamethyldisilazide orlithium diisopropylamide. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran. The reaction is generally carried outat temperatures of from -78° C. to 0° C. Generally, the reactionsrequire 1 to 72 hours. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme G, step 2, an appropriate nitrile bis-ester compoundof formula 35 is reduced and cyclized to give a 5-oxo-3-aryl-3-aceticacid ester pyrrolidine of formula 36.

For example, an appropriate nitrile bis-ester compound of formula 35 iscontacted with an appropriate reducing agent, such as sodium borohydridein the presence of cobalt II chloride hexahydrate or hydrogen in thepresence of a suitable catalyst, such as Raney nickel. For compounds offormula 35 in which Ar₁ is thienyl, sodium borohydride in the presenceof cobalt II chloride hexahydrate is preferred.

When sodium borohydride in the presence of cobalt chloride is used, thereaction is carried out in a suitable solvent, such as methanol, orethanol. The reaction is generally carried out at temperatures of from0° C. to 50° C. Generally, the reactions require 1 to 72 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction with aqueous acid, evaporation, trituration,chromatography, and recrystallization.

When Raney nickel is used, the reaction is carried out in a suitablesolvent containing ammonia, such as ethanol/ammonium hydroxide. Thereaction is generally carried out at temperatures of from ambienttemperature to 50° C. The reaction is carried out at pressures of from15 psi to 120 psi in an apparatus designed for carrying out reactionsunder pressure, such as a Parr hydrogenation apparatus. The product canbe isolated by carefully removing the catalyst by filtration andevaporation. The product can be purified by extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme G, step 3, an appropriate 5-oxo-3-aryl-3-acetic acidester pyrrolidine of formula 36 is hydrolyzed to give a5-oxo-3-aryl-3-acetic acid pyrrolidine of formula 37.

For example, an appropriate 5-oxo-3-aryl-3-acetic acid ester pyrrolidineof formula 36 is contacted with a suitable hydrolyzing agent, such assodium hydroxide, potassium hydroxide, or lithium hydroxide. Thereaction is carried out in a suitable solvent such as water,tetrahydrofuran/water mixtures, methanol, methanol/water mixtures, orethanol/water mixtures. The reaction is generally carried out attemperatures of from 0° C. to the refluxing temperature of the solvent.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme G, step 4, an appropriate 5-oxo-3-aryl-3-acetic acidpyrrolidine of formula 37 is reduced to give a5-oxo-3-aryl-3-(2-hydroxyethyl) pyrrolidine of formula 38.

For example, an appropriate 5-oxo-3-aryl-3-acetic acid pyrrolidine offormula 37 is contacted with a suitable borane reagent, such as boranedimethyl sulfide complex or sodium borohydride reduction of a mixedanhydride intermediate formed by methods well known in the art. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran.The reaction is generally carried out at a temperature of from 0° C. tothe refluxing temperature of the solvent. When complete the reaction isquenched by the careful addition of a suitable aqueous acid solution,such as 1M hydrochloric acid solution. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme G, step 5, an appropriate5-oxo-3-aryl-3-(2-hydroxyethyl) pyrrolidine of formula 38 is protectedusing dihydropyran to give a5-oxo-3-aryl-3-(2-THP-protected-hydroxyethyl) pyrrolidine of formula 39.

For example, an appropriate 5-oxo-3-aryl-3-(2-hydroxyethyl) pyrrolidineof formula 38 is contacted with dihydropyran. The reaction is carriedout in the presence of a catalytic amount of a suitable acid, such asp-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, or a sulfonicacid containing resin, such as Amberlyst H-15. The reaction is carriedout in a suitable solvent, such as dichloromethane. The reaction isgenerally carried out at ambient temperature. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

Reaction Scheme H

Reaction Scheme H is a general Scheme H for preparing intermediates forpreparing compounds of formula (1) wherein m is 2 and G₁ is --C(O)--.##STR23##

In Reaction Scheme H, optional step 1, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 39is alkylated with an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂,to an N-arylalkyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl)pyrrolidine of formula 40. An appropriate alkyl halide, X--CH₂--(CH₂)_(n) --Ar₂, is one in which X is chloro, bromo, or iodo; n is asdesired in the final product of formula (1), and Ar₂ is as desired informula (1).

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 39is contacted with from 1 to 5 molar equivalents of an appropriate alkylhalide, X--CH₂ --(CH₂)_(n) --Ar₂. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, ordimethylformamide. The reaction is carried out in the presence of abase, such as sodium hydride, sodium hexamethyldisilazide, potassiumt-butoxide, or lithium diisopropylamide with sodium hydride beingpreferred. The reaction is generally carried out at temperatures of from0° C. to the refluxing temperature of the solvent. Generally, thereactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme H, optional step 2, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 39is aroylated with an appropriate aroyl halide, aryl anhydride, or arylmixed anhydride, A-C(O)--(CH₂)_(n) --Ar₂, to anN-aroyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 41. An appropriate aroyl halide, aryl anhydride, or aryl mixedanhydride, A-C(O)--(CH₂)_(n) --Ar₂, is one in which A is an activatedleaving group, such as chloro or bromo, an anhydride, or mixedanhydride, n is as desired in the final product of formula (1), and Ar₂is as desired in formula (1).

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 39is contacted with 1 to 1.5 molar equivalents of an appropriate aroylhalide, aryl anhydride, or aryl mixed anhydride, A-C(O)--(CH₂)_(n)--Ar₂. The reaction is carried out in a suitable solvent, such astetrahydofuran, N,N-dimethylaniline, or diethyl ether. The reaction iscarried out in the presence of a base, such as sodium hydride,N,N-dimethylaniline, potassium t-butoxide, or lithium diisopropylamidewith sodium hydride being preferred. The reaction is generally carriedout at temperatures of from -20° C. to 50° C. Generally, the reactionsrequire 1 to 24 hours. The product can be isolated and purified bytechniques Well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme H, step 3, anN-arylalkyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 40 is deprotected to give anN-arylalkyl-5-oxo-3-aryl-3-(ω-hydroxyethyl) pyrrolidine of formula 16which gives rise to compounds of formula (1) in which G₁ is --C(O)--, G₂is --CH₂ --, m is 2, and n, Ar₁, and Ar₂ are as desired in the finalproduct of formula (1) or give rise after deprotection to Ar₁ as desiredin the final product of formula (1).

For example, anN-arylalkyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 40 is treated with a suitable acid, such as p-toluenesulfonicacid. The reaction is carried out in a suitable solvent, such asmethanol or ethanol. The product is isolated by evaporation and purifiedby techniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme H, step 4, anN-aroyl-5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 41 is deprotected, as taught above, to give anN-aroyl-5-oxo-3-aryl-3-(ω-hydroxyalkyl) pyrrolidine of formula 16 whichgives rise to compounds of formula (1) in which G₁ is --C(O)--, G₂ is--C(O)--, m is 2, and n, Ar₁, and Ar₂ are as desired in the finalproduct of formula (1) or give rise after deprotection to Ar₁ as desiredin the final product of formula (1).

Reaction Scheme I

Reaction Scheme I is a general scheme for preparing intermediates forpreparing compounds of formula (1) wherein m is 2 and G₁ is --C₂ --.##STR24##

In Reaction Scheme I, step 1, an appropriate5-oxo-3-aryl-3-(ωTHP-protected-hydroxyethyl)-prrolidine of formula 39 isreduced to give a 3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 44.

For example, an appropriate5-oxo-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 39is contacted with a suitable reducing agent, such as lithium aluminumhydride, aluminum hydride, or borane dimethyl sulfide complex. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran.The reaction is generally carried out at temperature of from 0° C. tothe refluxing temperature of the solvent. Generally, the reactionsrequire 1 to 72 hours. The product can be isolated and purified bytechniques well known in the art, such as quench of borane or aluminumcomplexes, extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme I, optional step 2, an appropriate3-aryl-3-(ω-THP-protected-hydroxyethyl)-pyrrolidine of formula 44 isalkylated with an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, toan N-arylalkyl-3-aryl-3-(ω-THP-protected-hydroxyethyl)-pyrrolidine offormula 45. An appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, isone in which X is chloro, bromo, or iodo; n is as desired in the finalproduct of formula (1), and Ar₂ is as desired in formula (1).

For example, an appropriate 3-aryl-3-(ω-THP-protected-hydroxyethyl)pyrrolidine of formula 45 is contacted with from 1.0 to 1.2 molarequivalents of an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂.The reaction is carried out in a suitable solvent, such astetrahydrofuran, dimethyl sulfoxide, acetonitrile, tetrahydrofuran,toluene, tetrahydrofuran/water mixtures, toluene/water mixtures, ordimethylformamide. The reaction is carried out in the presence of abase, such as sodium carbonate, potassium carbonate, sodium bicarbonate,triethylamine diisopropylethylamine, or pyridine. The reaction isgenerally carried out at temperatures of from 0° C. to the refluxingtemperature of the solvent. Generally, the reactions require 1 to 72hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme I, optional step 3, an appropriate3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula 44 isaroylated with an appropriate aroyl halide, aryl anhydride, or arylmixed anhydride, A-C(O)--(CH₂)_(n) --Ar₂, to anN-aroyl-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula46. An appropriate aroyl halide, aryl anhydride, or aryl mixedanhydride, A-C(O)--(CH₂)_(n) --Ar₂, is one in which A is an activatedleaving group, such as chloro or bromo, an anhydride, or mixedanhydride, n is as desired in the final product of formula (1), and Ar₂is as desired in formula (1).

For example, an appropriate 3-aryl-3-(ω-THP-protected-hydroxyethyl)pyrrolidine of formula 44 is contacted with 1 to 1.5 molar equivalentsof an appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,A-C(O)--(CH₂)_(n) --Ar₂. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, dichloromethane, acetonitrile,dimethylformamide, or pyridine. The reaction is carried out in thepresence of a base, such as sodium carbonate, potassium carbonate,sodium bicarbonate, triethylamine diisopropylethylamine, or pyridine.The reaction is generally carried out at temperatures of from -20° C. to50° C. Generally, the reactions require 1 to 24 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme I, step 4, anN-arylalkyl-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine offormula 45 is deprotected to give anN-arylalkyl-3-aryl-3-(ω-hydroxyethyl) pyrrolidine of formula 16 whichgives rise to compounds of formula (1) in which G₁ is --CH₂ --, G₂ is--CH₂ --, m is 2, n, Ar₁, and Ar₂ are as desired in the final product offormula (1) or give rise after deprotection to Ar₁ as desired in thefinal product of formula (1).

For example, an N-arylalkyl-3-aryl-3-(ω-THP-protected-hydroxyethyl)pyrrolidine of formula 16 is treated with a suitable acid, such asp-toluenesulfonic acid. The reaction is carried out in a suitablesolvent, such as methanol or ethanol. The product is isolated byevaporation and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme I, step 4, anN-aroyl-3-aryl-3-(ω-THP-protected-hydroxyethyl) pyrrolidine of formula46 is deprotected, as taught above, to give anN-aroyl-3-aryl-3-(ω-hydroxyethyl) pyrrolidine of formula 16 which givesrise to compounds of formula (1) in which G₁ is --CH₂ --, G₂ is--C(O)--, and m is 2, n, Ar₁, and Ar₂ are as desired in the finalproduct of formula (1) or give rise after deprotection to Ar₁ as desiredin the final product of formula (1).

Reaction Scheme J

Reaction Scheme J is an alternate scheme for preparing someintermediates giving rise to compounds of formula (1) wherein m is 2 andG₁ is --CH₂ -- and G₂ is --C(O)-- and for preparing some intermediatesgiving rise to compounds of formula (1) wherein m is 2 and G₁ is--C(O)-- and G₂ is --CH₂ --. ##STR25##

In Reaction Scheme J, optional step 1, an appropriate5-oxo-3-aryl-3-acetic acid ester pyrrolidine of formula 36 is reduced togive a 3-aryl-3-(ω-hydroxyethyl)pyrrolidine of formula 48.

For example, an appropriate 5-oxo-3-aryl-3-acetic acid ester pyrrolidineof formula 36 is contacted with a suitable reducing agent, such aslithium aluminum hydride, aluminum hydride, or borane dimethyl sulfidecomplex. The reaction is carried out in a suitable solvent, such astetrahydrofuran. The reaction is generally carried out at temperature offrom 0° C. to the refluxing temperature of the solvent. Generally, thereactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme J, step 2, an appropriate3-aryl-3-(ω-hydroxyethyl)-pyrrolidine of formula 48 is aroylated with anappropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,A-C(O)--(CH₂)_(n) --Ar₂, to anN-aroyl-3-aryl-3-(ω-hydroxyethyl)-pyrrolidine of formula 16. Anappropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,A-C(O)--(CH₂)_(n) --Ar₂, is one in which A is an activated leavinggroup, such as chloro, bromo, or iodo; an anhydride, or mixed anhydride,n is as desired in the final product of formula (1), and Ar₂ is asdesired in formula (1).

For example, an appropriate 3-aryl-3-(ω-hydroxyethyl) pyrrolidine offormula 48 is contacted with 1 to 1.1 molar equivalents of anappropriate aroyl halide, aryl anhydride, or aryl mixed anhydride,A-C(O)--(CH₂)_(n) --Ar₂. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, N,N-dimethylaniline, or diethyl ether.The reaction is carried out in the presence of a base, such asN,N-dimethylaniline, sodium hydride, potassium t-butoxide, or lithiumdiisopropylamide. The reaction is generally carried out at temperaturesof from --20° C. to 50° C. Generally, the reactions require 1 to 24hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme J, optional step 3, an appropriate5-oxo-3-aryl-3-acetic acid ester pyrrolidine of formula 36 is alkylatedwith an appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, to anN-arylalkyl-5-oxo-3-aryl-3-acetic acid ester pyrrolidine of formula 50.An appropriate alkyl halide, X--CH₂ --(CH₂)_(n) --Ar₂, is one in which Xis chloro, bromo, or iodo; n is as desired in the final product offormula (1), and Ar₂ is as desired in formula (1).

For example, an appropriate 5-oxo-3-aryl-3-acetic acid ester pyrrolidineof formula 36 is contacted with from 1.0 to 1.2 molar equivalents of anappropriate alkyl halide, X-CH₂ --(CH₂)_(n) --Ar₂. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran, dimethylsulfoxide, acetonitrile, or dimethylformamide. The reaction is carriedout in the presence of a base, such as sodium hydride, sodiumhexamethyldisilazide, potassium t-butoxide. The reaction is generallycarried out at temperatures of from 0° C. to 50° C. Generally, thereactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme J, step 4, an appropriateN-arylalkyl-5-oxo-3-aryl-3-acetic acid ester pyrrolidine of formula 50is hydrolyzed to give an N-arylalkyl-5-oxo-3-aryl-3-acetic acidpyrrolidine of formula 51.

For example, an appropriate N-arylalkyl-5-oxo-3-aryl-3-acetic acid esterpyrrolidine of formula 50 is contacted with a suitable hydrolyzingagent, such as sodium hydroxide, potassium hydroxide, or lithiumhydroxide. The reaction is carried out in a suitable solvent such aswater, tetrahydrofuran/water mixtures, methanol, methanol/watermixtures, or ethanol/water mixtures. The reaction is generally carriedout at temperatures of from 0° C. to the refluxing temperature of thesolvent. Generally, the reactions require 1 to 72 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chrommatography, andrecrystallization.

In Reaction Scheme J, step 5, an appropriateN-arylalkyl-5-oxo-3-aryl-3-acetic acid pyrrolidine of formula 51 isreduced to give a 5-oxo-3-aryl-3-(2-hydroxyethyl) pyrrolidine of formula16.

For example, an appropriate 5-oxo-3-aryl-3-acetic acid pyrrolidine offormula 51 is contacted with a suitable borane reagent, such as boranedimethyl sulfide complex. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran. The reaction is generally carried outat a temperature of from 0° C. to the refluxing temperature of thesolvent. When complete, the reaction is quenched by the careful additionof a suitable aqueous acid solution, such as 1M hydrochloric acidsolution. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

Alternately, an appropriate 5-oxo-3-aryl-3acetic acid pyrrolidine offormula 51 can be reduced by formation of a mixed anhydride intermediateand contacting the mixed anhydride intermediate with a suitable mildreducing agent, such as sodium borohydride to give5-oxo-3-aryl-3-(2-hydroxyethyl) pyrrolidine of formula 16.

For example, an appropriate 5-oxo-3-aryl-3-acetic acid pyrrolidine offormula 51 is contacted with 1.2 to 1.7 equivalents of a suitable base,such as N-methylmorpholine, in a suitable solvent, such astetrahydrofuran or diethyl ether. The reaction mixture is cooled to atemperature of between -50° C. and 0° C. with -25° C. to -20° C. beingpreferred, before the addition of 1.2 to 1.7 equivalents of isobutylchloroformate. The reaction is allowed to stir for 30 minutes to 3 hoursto allow for the formation of the mixed anhydride. After the formationof the mixed anhydride is complete, sodium borohydride is added. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

Reaction Scheme K

Reaction Scheme K is a general route for preparing some piperidinecompounds of formula 18 which give rise to compounds of formula (1) inwhich Y₁ is --C(O)NHR₅, --C(O)NR₆ R₇, or --C(O)NR₈ R₉ and Y₂ is aradical chosen from the group ##STR26##

In Reaction Scheme K, step 1, an appropriate protectedbis-(2-chloroethyl)-amine of formula 60 is alkylated with an appropriatearyl acetonitrile of formula 61 to give an protected4-aryl-4-cyano-piperidine of of formula 62. An appropriate protectedbis-(2-chloroethyl)-amine of formula 60 is one in which the protectinggroup, Pg₁, may be C₁ -C₄ alkyl, benzyl, substituted benzyl, tosyl,benzenesulfonyl, or a carbamate, such as t-butoxycarbonyl orethoxycarbonyl. An appropriate aryl acetonitrile of formula 61 is one inwhich Y₂ is as desired in the final product of formula (1). Alkylationsof this type are well known and appreciated in the art, T. Cammack andP. C. Reeves, J. Heterocyclic Chem. 23, 73-75 (1986) and C. V. Bercz andR. D. Ice, J. Pharmaceutical Sci., 61, 1316-1317 (1972).

For example, an appropriate protected bis-(2-chloroethyl)-amine offormula 60 is contacted with an appropriate aryl acetonitrile of formula61. The reaction is carried out in the presence of a base, such assodium amide, sodium hydride, sodium hexamethyldisilazide, potassiumt-butoxide, and lithium diisopropylamide. The reaction is carried out ina solvent, such as dimethyl sulfoxide and tetrahydrofuran. The reactioncan be carried out in the presence of 0.01 to 0.5 molar equivalents of asuitable catalyst, such as sodium iodide or potassium iodide. Thereaction is generally carried out at temperatures of from 0° C. to 80°C. Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

Alternately, for example, an appropriate protectedbis-(2-chloroethyl)-amine of formula 60 is contacted with an appropriatearyl acetonitrile of formula 61 under phase transfer conditions. Thereaction is carried out in a solvent system consisting of an organicphase and an aqueous phase. The reaction is carried out in the presenceof a hydroxide base, such as sodium hydroxide or potassium hydroxide.The reaction is carried out in the presence of a suitable catalystincluding quaternary ammonium and phosphonium salts, such astetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate,benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide,and the like. The reaction is vigorously stirred and is generallycarried out at temperatures of between 020 C. and 100° C. Generally, thereactions require 1 to 24 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme K, optional step 2, a protected4-aryl-4-cyano-piperidine of formula 62 is deprotected to give a4-aryl-4-cyano-piperidine of formula 62a. The removal of amineprotecting groups is well known and appreciated in the art and isdescribed in Protecting Groups in Organic Synthesis by T. Greene,Wiley-Interscience (1981). The removal of the amine protecting groupPg₁, in this step may be required when Pg₁ is benzyl to allow thehydrolysis of the nitrile to the acid in step 3.

In Reaction Scheme K, step 3, a 4-aryl-4-cyano-piperidine of formula 62ais hydrolyzed to a 4-aryl-4-carboxylic acid-piperidine of formula 63.The hydrolysis of nitriles to acids may be carried out under acidic orbasic conditions as is well known and appreciated in the art.

In Reaction Scheme K, step 4, a 4-aryl-4-carboxylic acid-piperidine ofof formula 63 is protected to give a protected 4-aryl-4-carboxylicacid-piperidine of formula 63a. The selection and use of amineprotecting groups, Pg₂, is well known and appreciated in the art and isdescribed in Protecting Groups in Organic Synthesis by T. Greene,Wiley-Interscience (1981).

In Reaction Scheme K, optional step 5, a protected4-aryl-4-cyano-piperidine of of formula 62 is hydrolyzed to a aprotected 4-aryl-4-carboxylic acid-piperidine of of formula 63a. Thehydrolysis of nitriles to acids may be carried out under acidic or basicconditions as is well known and appreciated in the art. The selectionand use of hydrolysis conditions which are compatible with theprotecting groups, Pg₁, is well known and appreciated in the art. Forprotected 4-aryl-4-carboxylic acid-piperidine of formula 63a prepared byScheme K, optional step 5, the protecting groups Pg₁ and Pg₂ arenecessarily the same protecting group.

In Reaction Scheme K, step 6, a protected 4-aryl-4-carboxylicacid-piperidine of formula 63a undergoes an amidation reaction with anappropriate amine, NHRR, to give a protected 4-aryl-4-carboxylic acidamide-piperidine of formula 64. An appropriate amine, NHRR, includesamines of the formulas NH₂ R₅, NHR₆ R₇, or NHR₈ R₉, in which R₅, R₆ andR₇, and R₈ and R₉ are as desired in the final compound of formula (1).

An amidation reaction may proceed through the acid of formula 63a or theacid function of a compound of formula 63a may be first converted to anactivated intermediate; such as an anhydride; a mixed anhydride ofsubstituted phosphoric acid, such as dialkylphosphoric acid,diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylicacid, such as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroaceticacid, trifluoroacetic acid, and the like; of aromatic carboxylic acids,such as benzoic acid and the like; an activated ester, such as phenolester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenolester, pentachlorophenol ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester, and thelike; activated amide, such as imidazole, dimethylpyrazole, triazole, ortetrazole; or the intermediate formed in the presence of couplingagents, such as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Activated intermediatesmay be prepared and used directly, or are prepared and isolated beforethe addition of an appropriate amine, NHRR of the formulas NH₂ R₅, NHR₆R₇, or NHR₈ R₉. Alternately, activated intermediates may be preparedisolated and purified before the addition of an appropriate amine, NHRRof the formulas NH₂ R₅, NHR₆ R₇, or NHR₈ R₉. The use and formation ofactivated intermediates is well known and appreciated in the art.

For example, an acid compound of formula 63a is contacted with a slightmolar excess of an appropriate amine, NHRR of the formulas NH₂ R₅, NHR₆R₇, or NHR₈ R₉, or a salt of an appropriate amine and1-hydroxybenzotriazole hydrate in the presence of a slight molar excessof a coupling agent, such as dicyclohexylcarbodiimide or1-(3-dimethyaminopropyl)-3-ethylcarbodiimide. The reaction is carriedout in the presence of a suitable base, such as diisopropylethyl amine,if the salt of an amine is used an additional equimolar molar amount ofa suitable base is added. The reaction is carried out in a suitablesolvent, such as dichloromethane or chloroform. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, chromatography, and recrystallization.

Alternatively, for example, an acid of formula 63a is contacted with 1.2to 1.7 equivalents of a suitable base, such as N-methylmorpholine, in asuitable solvent, such as tetrahydrofuran. The reaction mixture iscooled to a temperature of between -50° C. and 0° C. with -25° C. to-20° C. being preferred, before the addition of 1.2 to 1.7 equivalentsof isobutyl chloroformate. The reaction is allowed to stir for 30minutes to 3 hours to allow for the formation of the mixed anhydride, anactivated intermediate. While maintaining the temperature at between-50° C. and 0° C. an appropriate amine, NHRR of the formulas NH₂ R₅,NHR₆ R₇, or NHR₈ R₉, is added, if the salt of an appropriate amine isused an additional equimolar molar amount of a suitable base is added.The reaction may, after the addition of amine is complete, be warmed toroom temperature. Generally, the reaction requires from 2 to 48 hours.The product can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

In Reaction Scheme K, step 7 a protected 4-aryl-4-carboxylic acidamide-piperidine of formula 64 is deprotected to give a piperidine offormula 18. The removal of amine protecting groups is well known andappreciated in the art and is described in Protecting Groups in OrganicSynthesis by T. Greene, Wiley-Interscience (1981).

Reaction Scheme K.1

Reaction Scheme K.1 is a general route for preparing some piperidinecompounds of formula 18 which give rise to compounds of formula (1) inwhich Y₁ is --C(O)NHR₅ in which R₅ is hydrogen and Y₂ is a radicalchosen from the group ##STR27##

In Reaction Scheme K.1, step 1, an appropriate 4-aryl-4-cyano-piperidineof formula 62b is hydrolyzed to a 4-aryl-4-carboxylic acidamide-piperidine N-oxide of formula 62c.

An appropriate 4-aryl-4-cyano-piperidine of formula 62b is one in whichthe protecting group, Pg₆ is benzyl or substituted benzyl and Y₂ is asdesired in the final product of formula (1). Appropriate4-aryl-4-cyano-piperidines of formula 62b are readily available asdescribed in Reaction Scheme K and may also be obtained by benzylationof a 4-aryl-4-cyano-piperidine of formula 62a using a suitable benzylhalide or substituted benzyl halide as is well known in the art.

For example, an appropriate 4-aryl-4-cyano-piperidine of formula 62b iscontacted with basic hydrogen peroxide. Reagents for Organic Synthesis,Fieser and Fieser, John Wiley and Sons, Inc. (1967). Alkali metalhydroxides, such as sodium hydroxide or potassium hydroxide are suitablebases for this reaction. The reaction is carried out in a suitablesolvent, such as ethanol or methanol. The reaction is carried out attemperatures of from 0° C. to the refluxing temperature of the suitablesolvent. Generally, the reaction requires from about 4 hours to 4 days.The product can be isolated and purified by techniques well known in theart, such as extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme K.1, step 2, an appropriate 4-aryl-4-carboxylic acidamide-piperidine N-oxide of formula 62c is deprotected and reduced togive a piperidine of formula 18 wherein Y₁ is --C(O)NHR₅ in which R₅ ishydrogen.

The removal of amine protecting groups, such as benzyl and substitutedbenzyl is well known and appreciated in the art and is described inProtecting Groups in Organic Synthesis by T. Greene, Wiley-Interscience(1981). The reduction of amine oxides is also well known in the art. Itis understood that the amine deprotection and amine oxide reduction maybe carried out at the same time or may be carried out sequentially.

Reaction Scheme L

Reaction Scheme L is a general route for preparing some piperidinecompounds of formula 18 which give rise to compounds of formula (1) inwhich Y₁ is --C(O)NHR₅, --C(O)NR₆ R₇, or --C(O)NR₈ R₉ and Y₂ is aradical chosen from the group ##STR28##

In Reaction Scheme L, step 1, piperidine-4-carboxylic acid ethyl ester,compound 66 is protected to give a protected piperidine-4-carboxylicacid ethyl ester of formula 67. The selection and use of amineprotecting groups, Pg₃, is well known and appreciated in the art and isdescribed in Protecting Groups in Organic Synthesis by T. Greene,Wiley-Interscience (1981). The use of carbamate protecting groups, suchas benzyloxycarbonyl and t-butoxycarbonyl is preferred.

In Reaction Scheme L, step 2, a protected piperidine-4-carboxylic acidethyl ester of formula 67 is reacted with an appropriate benzylatingagent to give a protected 4-benzylated-piperidine-4-carboxylic acidethyl ester of formula 68. An appropriate benzylating agent is one whichtransfers an benzyl or substituted benzyl in which R₁₀ is as desired inthe final product of formula (1).

For example, a protected piperidine-4-carboxylic acid ethyl ester offormula 67 is contacted with from 1.0 to 3.0 molar equivalents of benzylhalide or a substituted benzyl halide. The reaction is carried out inthe presence of 1.0 to 1.5 molar equivalents of a suitable base, such assodium hexamethyldisilazide, sodium hydride, potassium t-butoxide, orlithium diisopropylamide. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, dimethylformamide, or dimethylsulfoxide. The reaction is generally carried out at temperatures of from-78° C. to 0° C. Generally, the reactions require 1 to 24 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme L, step 3, a protected4-benzylated-piperidine-4-carboxylic acid ethyl ester of formula 68 ishydrolyzed to give a protected 4-benzylated-piperidine-4-carboxylic acidof formula 69.

For example, a protected 4-benzylated-piperidine-4-carboxylic acid ethylester of formula 68 is contacted with a suitable hydrolyzing agent, suchas sodium hydroxide, potassium hydroxide, or lithium hydroxide. Thereaction is carried out in a suitable solvent such as water,tetrahydrofuran/water mixtures, methanol, methanol/water mixtures, orethanol/water mixtures. The reaction is generally carried out attemperatures of from 0° C. to the refluxing temperature of the solvent.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme L, step 4, a protected4-benzylated-piperidine-4-carboxylic acid of formula 69 undergoes anamidation reaction; as generally taught in Reaction Scheme K, step 6;with an appropriate amine, NHRR, to give a protected4-benzylated-piperidine-4-carboxylic acid amide of formula 70. Anappropriate amine, NHRR, includes amines of the formulas NH₂ R₅, NHR₆R₇, or NHR₈ R₉, in which R₅, R₆ and R₇, and R₈ and R₉ are as desired inthe final compound of formula (1).

In Reaction Scheme L, step 5, a protected4-benzylated-piperidine-4-carboxylic acid amide of formula 70 isdeprotected to give a 4-benzylated-piperidine-4-carboxylic acid amide offormula 18 in which Y₁ is --C(O)NHR₅, --C(O)NR₆ R₇, or --C(O)NR₈ R₉ andY₂ benzyl or substituted benzyl. The removal of amine protecting groupsis well known and appreciated in the art and is described in ProtectingGroups in Organic Synthesis by T. Greene, Wiley-Interscience (1981).

Reaction Scheme M

Reaction Scheme M is a general routes for preparing piperidine compoundsof formula 18 which give rise to compounds of formula (1) in which Y₁and Y₂ together with their attached carbon form a spirocyclic ringchosen from the group ##STR29## Some of the piperidine compounds offormula 18 in which Y₁ and Y₂ together with their attached carbon form aspirocyclic ring are known in the art or can be prepared by methodsknown analogously in the art. P. L. Feldman and M. F. Bracken JOC 55,4207-4209 (1990); L. D. Wise et al. J. Med. Chem. 28, 1811-1817 (1985);and G. M. Carrera, Jr. and D. S. Garvey, J. Heterocyclic Chem. 29,847-850 (1992). ##STR30##

In Reaction Scheme M, step 1, a protected piperidin-4-one of formula 71is condensed with the appropriate aniline to give a protected imine offormula 72. An appropriate 72 aniline is one in which gives rise to animine of formula in which R₁₂ is as is desired in the final compound offormula (1). Generally, the protected imine of formula 72 is notisolated before it is converted to the protected 4-cyano piperidine offormula 73. The formation of protected imines of formula 72 is wellknown and appreciated in the art.

In Reaction Scheme M, step 2, a protected imine of formula 72 isconverted to a protected 4-cyano piperidine of formula 73. A protectedimine of formula 72 is contacted with a reagent which causes it toundergo a Strecker reaction, such as hydrogen cyanide, potassiumcyanide, sodium cyanide, acetone cyanohydrin, or trimethylsilyl cyanide.The conditions used depend on the method chosen for carrying out theStrecker reaction. The Strecker reaction and the choice of conditionsfor carrying out the Strecker reaction are well known and appreciated inthe art.

In Reaction Scheme M, optional step 3, a protected 4-cyano piperidine offormula 73 is converted to a protected1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula 74.

For example, a protected 4-cyano piperidine of formula 73 is contactedwith an equimolar amount of chlorosulfonyl isocyanate to give anunpurified intermediate. The reaction is carried out in a suitablesolvent, such as dichloromethane. Generally, the reaction is carried outat temperatures of from 0° C. to 50° C. The reaction generally requiresfrom 10 minutes to 3 hours. The unpurified intermediate is recovered byevaporation in vacuo. The unpurified intermediate is contacted with asuitable aqueous acid, such as 1M hydrochloric acid, and is heated tofrom 50° C. to the refluxing temperature of the suitable aqueous acid.The reaction generally requires from 30 minutes to 4 hours. The productcan be isolated and purified by techniques well known in the art, suchas cooling, adjusting of pH, extraction, evaporation, chromatography,and recrystallization.

In Reaction Scheme M, optional step 4, a protected1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula 74 isdeprotected to give a 1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione offormula 75. The removal of amine protecting groups is well known andappreciated in the art and is described in Protecting Groups in OrganicSynthesis by T. Greene, Wiley-Interscience (1981); R. A Olofson, JOC 49,2936-2938 (1991); and Y-K. Shue et al., JOC 56, 2936-2938 (1991).

In Reaction Scheme M, optional step 5, a protected1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula 74 isbenzylated or alkylated with an appropriate benzylating or alkylatingagent to give a protected3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula76. An appropriate benzylating or alkylating agent is one whichtransfers a benzyl, substituted benzyl, or C₁ -C₆ alkyl as is requiredin R₁₃ in the final product of formula (1).

For example, a protected 1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dioneof formula 74 is contacted with 1.0 to 3.0 molar equivalents of anappropriate benzylating or alkylating agent, such as benzyl halide, asubstituted benzyl halide, or a C₁ -C₆ alkyl halide. The reaction iscarried out in the presence of 1.0 to 1.5 molar equivalents a suitablebase, such as sodium hydroxide, potassium hydroxide, sodiumhexamethyldisilazide, sodium hydride, potassium t-butoxide, or lithiumdiisopropylamide. The reaction is carried out in a suitable solvent,such as tetrahydrofuran, ethanol, dimethylformamide, or dimethylsulfoxide. The reaction is generally carried out at temperatures of from0° C. to the refluxing temperature of the solvent. Generally, thereactions require 1 to 24 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme M, step 6, a protected3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula76 is deprotected to give a3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione of formula77. The removal of amine protecting groups is well known and appreciatedin the art and is described in Protecting Groups in Organic Synthesis byT. Greene, Wiley-Interscience (1981); R. A Olofson, JOC 49, 2936-2938(1991); and Y-K. Shue et al., JOC 56, 2936-2938 (1991).

In Reaction Scheme M, optional step 7, a protected 4-cyano-piperidine offormula 73 is hydrolyzed to give a protected piperidine-4-carboxylicacid amide of formula 78. The hydrolysis of nitriles to carboxylic acidamides under acidic conditions is well known and appreciated in the art.

In Reaction Scheme M, step 8, a protected piperidine-4-carboxylic acidamide of formula 78 is converted to a protected1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one of formula 79.

For example, a protected piperidine-4-carboxylic acid amide of formula78 is contacted with an excess of dimethoxy-N,N-dimethylmethanamine. Thereaction is carried out in a suitable solvent, such as toluene.Generally, the reaction is carried out at temperatures of from ambienttemperature to the refluxing temperature of the solvent. The reactionsgenerally require from 12 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme M, optional step 9, a protected1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one of formula 79 isdeprotected to give a 1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one offormula 80. The removal of amine protecting groups is well known andappreciated in the art and is described in Protecting Groups in OrganicSynthesis by T. Greene, Wiley-Interscience (1981); R. A Olofson, JOC 49,2936-2938 (1991); and Y-K. Shue et al., JOC 56, 2936-2938 (1991).

In Reaction Scheme M, optional step 10, a protected1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one of formula 79 is reducedto a 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 81 or aprotected 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 82. A1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 81 is the productof Reaction Scheme M, optional step 10, when Pg₄ is a protecting groupwhich is removed be hydrogenation, such as benzyl or substituted benzyl.A protected 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 82 isthe product of Reaction Scheme M, optional step 10, when a hydrogenationstable protecting group, such as methyl is used. For protected1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 82 prepared byScheme M, optional step 10, the protecting groups Pg₄ and Pg₅ arenecessarily the same protecting group.

For example, a protected 1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-oneof formula 79 is contacted with hydrogen in the presence Of a suitablecatalyst, such as 5% platinum-on-carbon, 10% platinum-on-carbon, 5%palladium-on-carbon, 10% palladium-on-carbon, Pearlman's catalyst,platinum oxide, and palladium oxide. The reaction is carried out in asuitable solvent, such as ethanol, methanol, ethyl acetate, and water.The reaction is generally carried out at temperatures of from ambienttemperature to 50° C. The reaction is carried out at pressures of from15 psi to 120 psi in an apparatus designed for carrying out reactionsunder pressure, such as a Parr hydrogenation apparatus. The product canbe isolated by carefully removing the catalyst by filtration andevaporation. The product can be purified by extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme M, step 11, a1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 81 is protected togive a protected a 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula82. The selection and use of suitable amine protecting groups is wellknown and appreciated in the art and is described in Protecting Group inOrganic Synthesis by T. Greene, Wiley-Interscience (1981).

In Reaction Scheme M, step 12, a protected1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 82 is isbenzylated or alkylated with an appropriate benzylating or alkylatingagent to give a protected3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 83.An appropriate benzylating or alkylating agent is one which transfers abenzyl, substituted benzyl, or C₁ -C₆ alkyl as is required in R₁₃ in thefinal product of formula (1).

For example, a protected 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one offormula 82 is contacted with 1.0 to 3.0 molar equivalents of anappropriate benzylating or alkylating agent, such as benzyl halide, asubstituted benzyl halide, or a C₁ -C₆ alkyl halide. The reaction iscarried out in the presence of 1.0 to 1.5 molar equivalents a suitablebase, such as sodium hexamethyldisilazide, sodium hydride, potassiumt-butoxide, or lithium diisopropylamide. The reaction is carried out ina suitable solvent, such as tetrahydrofuran, dimethylformamide, ordimethyl sulfoxide. The reaction is generally carried out attemperatures of from -10° C. to the refluxing temperature of thesolvent. Generally, the reactions require 1 to 72 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme M, step 13, a protected3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 83is deprotected to give a3-substituted-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one of formula 84.The removal of amine protecting groups is well known and appreciated inthe art and is described in Protecting Groups in Organic Synthesis by T.Greene, Wiley-Interscience (1981).

EXAMPLE 1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

1.1 Synthesis of 3-cyano-3-(3,4-dichloro-phenyl)-pentanedioic diethylester (No.027F126)

3,4-Dichlorophenylacetonitrile (10 g, 53.75 mmol) was stirredmechanically in THF (50 mL) at -78° C. and treated dropwise with sodiumbis-(trimethylsilyl)amide (108 mL, 1M; 2 eq.). The reaction slurry wasallowed to warm to 20° C. and stirred for 3 hours. The solution wascooled to -78° C. and the slurry was treated with ethyl bromoacetate (12mL, 107 mmol, 2 eq.). The slurry was again allowed to warm to 20° C. andstirred 18 hours. The slurry was dissolved in ethyl ether and washedwith water and brine. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (400 g) with 20% ethyl acetate to give15.85 g (82%) of the title compound.

1.1.1 Synthesis of 3-cyano-3-(3,4-dichloro-phenyl)-pentanedioic diethylester

Sodium bis-(trimethylsilyl)amide (7910 mL, 1M, 7910 mmol) was cooled to0° C. A solution of 3,4-dichlorophenylacetonitrile (700 g, 3763 mmol) inTHF (2.50 L) was added maintaining the temperature of the reactionmixture between 0° and 20° C. After 1 hour, the above solution is addedby candula to a solution of ethyl bromoacetate (910 mL) in THF (1.40 L)cooled to 0° C. The addition is carried out at such a rate that thetemperature of the reaction mixture does not rise above 20° C. After 15minutes, the reaction was quenched by the addition of t-butyl methylether (7.0 L) and water (3.5 L). The organic layer was separated and wasextracted with water, 5% NaHCO₃, and brine. The organic layer was driedover MgSO₄, filtered, and concentrated in vacuo to obtain a residue. Theresidue was recrystallized from diethyl ether to give the titlecompound: mp=69°-71° C.

1.1.2 Synthesis of 3-cyano-3-(3,4-dichloro-phenyl)-pentanedioic aciddiethyl ester

3,4-Dichlorophenylacetonitrile (30.0 g, 0.161 mol) and THF (100 mL) werecombined and cooled in a dry-ice/acetone bath. Sodiumbis-(trimethylsilyl)amide (324 mL, 1.0M in THF, 0.324 mol, 2 eq.) wasadded dropwise. After the addition was complete, the mixture was allowedto warm to ambient temperature. After 4 h, the mixture was cooled in adry-ice/acetone bath. Ethyl bromoacetate (36 mL, 0.325 mol) was addeddropwise. After the addition was complete, the mixture was allowed towarm to ambient temperature. The reaction mixture was partitionedbetween diethyl ether and water. The organic layer was extracted with H₂O (3×150 mL), 1N HCl (2×100 mL), 5% NaHCO₃ (2×100 mL), and brine (1×150mL). The organic layer was dried over MgSO₄, filtered, and concentratedin vacuo to obtain a residue. The residue was recrystallized fromdiethyl ether to give the title compound:

R_(f) =0.28 (silica gel, 20% ethyl acetate in hexane), mp=68°-69° C.

Analysis: calculated for C₁₆ H₁₇ Cl₂ NO₄ C 53.65; H 4.78; N 3.91; FoundC 53.69; H 4.79; N 3.93.

1.2 Synthesis of [3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-aceticacid ethyl ester (No.027F128)

3-Cyano-3-(3,4-dichloro-phenyl)-pentanedioic acid diethyl ester (10 g;27.94 mmol) was dissolved in methanol (100 mL) and cobalt(II)chloridehexahydrate (13.2 g, 55.48 mmol) was added. The solution was thencautiously treated with one gram portions of sodium borohydride (11 g,290 mmol) over 45 minutes at 20°-30° C. The solution was allowed to stiran additional 1.5 hours and the solution was concentrated in vacuo. Theresidue was partitioned between dichloromethane and 1N HCl the organicphase was and washed with 1N HCl (700 mL). The organic phase was driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas chromatographed on silica gel (600 g) with a gradient of 3% to 6%methanol in dichloromethane to give 7.514 g (85%) of the title compound.

1.2.2 Synthesis of[3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester

3-Cyano-3-(3,4-dichloro-phenyl)-pentanedioic acid diethyl ester (32 g,89.4 mmol) and ethanol (150 mL) were combined. The mixture was added toRaney nickel (100 g) in a Parr bottle and NH₄ OH (40 mL) was added. Thereaction was hydrogenated in a Parr shaker at 50 psi for 24 h. Theslurry was filtered through a celite pad and the solids were rinsed withethanol. The filtrate was concentrated in vacuo to obtain a residue. Theresidue was chromatographed on silica gel (400 g) eluting with 6%methanol in dichloromethane to give the title compound:

R_(f) =0.34 (silica gel, 6% methanol in dichloromethane), mp=87°-90° C.

Analysis: calculated for C₁₄ H₁₅ Cl₂ NO₃ C 53.18; H 4.78; N 4.43; FoundC 53.34; H 4.71; N 4.51.

1.3 Synthesis of[3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (No.027F129)

Lithium aluminum hydride (4.0 g, 105 mmol) was stirred in THF (20 mL)and [3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidiny-3-yl]-acetic acid ethylester (7.51 g, 23.79 mmol) was added dropwise in THF (50 mL). The slurrywas heated to reflux and allowed to stir for 21 hours. The slurry wascooled in an ice bath and sequentially treated dropwise with water (4mL), 15% NaOH (4 mL), and water (12 mL). The slurry was allowed to stirfor 3 hours at 20° C. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 6.37 g of the titlecompound.

1.3.2 Synthesis of 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol

A solution of LiAlH₄ (450 mL, 1M in THF, 450 mmol) was cooled in aice/acetone bath (-10° C.). A solution of H₂ SO₄ (99.999%) (12 mL, 225.3mmol) in THF (35 mL) was added dropwise. (Use caution when adding the H₂SO₄ to the THF and also when adding the H₂ SO₄ /THF solution to theLiAlH₄.) After the addition was complete, the slurry was stirred for 1 hin an ice bath. The slurry was allowed to warm to ambient temperatureand stir for 2 h. A solution of[3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester(23.2 g, 73.4 mmol) in THF (70 mL) was added dropwise. The slurry washeated to 45°-50° C. for 36 h. The slurry was cooled in an ice bath anda solution of THF:H₂ O (1:1, 70 mL) was added dropwise. The slurry wasfiltered and the solids were rinsed with THF and dichloromethane. Thesalts were stirred with THF:H₂ O:15% NaOH (1 L: 70 mL: 20 mL) for 2 h.The slurry was filtered and the combined filtrates were concentrated invacuo to obtain a residue. The residue was dissolved in dichloromethaneand the solution was dried over MgSO₄, filtered, and concentrated invacuo to obtain a residue. The residue was recrystallized from diethylether to give the title compound:

R_(f) =0.27 (silica gel, 9:1:0.2; dichloromethane:methanol:ammoniumhydroxide), mp=91°-94° C.

Analysis: calculated for C₁₂ H₁₅ Cl₂ NO C 55.40; H 5.81; N 5.38; Found C55.64; H 5.88; N 5.20.

1.4 Synthesis of3-(3,4-dichloro-phenyl)-1-(benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (6.37 g, 24.5mmol) was dissolved in dichloromethane (100 mL) at -78° C. and treatedwith 4-methylmorpholine (5.5 mL, 50 mmol, 2.0 eq.) and benzoyl chloride(3.0 mL, 25.8 mmol, 1.05 eq.). The solution was allowed to warm to 0° C.and stir for 2 hours. The reaction mixture was washed with 1N HCl and 5%NaHCO₃, and the organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel (300 g) with a gradient from ethyl acetate to 10% methanol indichloromethane to give 6.32 g (71%) of the title compound.

1.5 Synthesis of2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(No.027F42)

3-(3,4-Dichloro-phenyl)-1-(benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine (220mg, 0.6 mmol) was dissolved in dichloromethane (4 mL) andN,N-diisopropylethylamine (0.13 mL, 0.75 mmol, 1.24 eq.) andmethanesulfonyl chloride (0.055 mL, 0.71 mmol, 1.18 eq.) were added at0° C. The solution was allowed to stir at 0° C. for 3 hours. Thesolution was diluted with dichloromethane and washed with 1N HCl, 5%sodium bicarbonate and water. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (30 g), with a gradient of 50% ethylacetate in hexane to 75% ethyl acetate in hexane to give 191 mg (72%) ofthe title compound.

1.6 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (No.027F42)

2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]ethylmethanesulfonate (191 mg, 0.43 mmol) was treated with the4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (144 mg, 0.599mmol) and NaHCO₃ (90 mg, 1.07 mmol, 2.5 eq.) in THF/H₂ O (5 mL/1 mL) atreflux for 21 hours. The solution was concentrated in vacuo and theaqueous phase was extracted with dichloromethane. The organic phase wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was chromatographed on silica gel (30 g) with 6% methanol indichloromethane to give 146 mg (44%).

Exact mass (Cl): calculated for C₃₁ H₃₃ Cl₂ N₃ O₂ (M+): 549.1950. Found549.1920.

EXAMPLE 2

Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

2.1 Synthesis of[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F108)

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1mmol) was dissolved in dichloromethane (3 mL) at -78° C. and treatedwith 4-methylmorpholine (0.25 mL, 2.27 mmol, 2.eq.) and2,4-dimethoxy-benzoyl chloride (220 mg, 1.1 mmol, 1 eq.) dissolved in 3mL of dichloromethane. The solution was allowed to warm to 0° C. andstirred for 1 hour. The solution was washed with 1N HCl and 5% sodiumbicarbonate. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6%methanol in dichloromethane to give 324 mg (69%) of the title compound.

2.2 Synthesis of2-[1-(2,4-dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(No.027F117)

3-(3,4-Dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(320 mg, 0.75 mmol) was dissolved in dichloromethane (5 mL) andN,N-diisopropylethylamine (0.35 mL, 2.0 mmol, 2.7 eq.) andmethanesulfonyl chloride (0.080 mL, 1.0 mmol, 1.4 eq.) were addeddropwise at 0° C. and allowed to stir for 3 hours. The solution wasdiluted with dichloromethane and washed with 1N HCl and 5% sodiumbicarbonate. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel (30 g) with 6% methanol in dichloromethane to give. 343 mg(91%) of the title compound.

2.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(2,4-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (No.027F117).

2-[1-(2,4-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(343 mg, 0.68 mmol) was dissolved in THF (8 mL) and the4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (170 mg, 0.71mmol, 1.04 eq.), potassium carbonate (200 mg, 1.45 mmol, 2.1 eq.), andwater (2 mL) were added and the solution was heated at reflux for 16hours. The solution was concentrated in vacuo and the aqueous phase wasextracted with dichloromethane, dried over magnesium sulfate, filtered,and concentrated in vacuo. The residue was chromatographed on silica gel(40 g) with a gradient of ethyl acetate to 6% methanol indichloromethane to give 151 mg (36%) of the title compound.

Analysis: calculated for C₃₃ H₃₇ Cl₂ N₃ O₄.0.6 H₂ O C 63.86; H 6.20; N6.76. Found C 63.61; H 6.13; N 6.67.

EXAMPLE 3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

3.1 Synthesis of[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F109)

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1mmol) was dissolved in dichloromethane at -78° C. and treated with4-methylmorpholine (0.25 mL, 2.27 mmol, 2 eq.) and3,4,5-trimethoxy-benzoyl chloride (250 mg, 1.1 mmol, 1 eq) indichloromethane (3 mL). The solution was allowed to warm to 0° C. andstir for 1 hour. The solution was washed with 1N HCl and 5% sodiumbicarbonate and the organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6%methanol in dichloromethane to give 353 mg (71%) of the title compound.

3.1.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

2-[3-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (5.885 g, 22.64mmol) and dichloromethane (135 mL) were combined. 4-Methylmorpholine(5.0 mL, 45.48 mmol, 2 eq.) was added. The mixture was cooled in adry-ice/acetone bath and a solution of 3,4,5-trimethoxy-benzoyl chloride(5.22 g, 22.63 mmol) in dichloromethane (100 mL) was added dropwise.After the addition was complete, the dry-ice/acetone bath was changed toan ice bath and the mixture was stirred for 1 h. The solution wasextracted with 1N HCl (50 mL), 5% NaHCO₃ (50 mL), and H₂ O (50 mL). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuoto obtain a residue. The residue was purified by chromatography onsilica gel (400 g) eluting with ethyl acetate and then 6% methanol indichloromethane to give the title compound:

R_(f) =0.38 (silica gel, 6% methanol in dichloromethane).

3.2 Synthesis of2-[3,4-(dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]ethyl methanesulfonate (No.027F116)

3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(350 mg, 0.77 mmol, was dissolved in dichloromethane (5 mL) andN,N-diisopropylethylamine (0.35 mL, 2.0 mmol, 2.6 eq.) andmethanesulfonyl chloride (0.080 mL, 1.03 mmol, 1.34 eq.) were addeddropwise at 0° C. The solution was allowed to stir for 1 hour at 0° C.The solution was diluted with dichloromethane and washed with 1N HCl and5% sodium bicarbonate. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (30 g) with a gradient of ethyl acetate to6% methanol in dichloromethane to give 376 mg (92%) of the titlecompound.

3.2.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(3.5 g, 7.87 mmol) and dichloromethane (100 mL) were combined.N,N-diisopropylethylamine (3.0 mL, 17.22 mmol, 2.2 eq.) was added andthe mixture was cooled in an ice bath. Methanesulfonyl chloride (0.82mL, 10.59 mmol, 1.35 eq.) was added dropwise. After the addition, themixture was stirred 1.5 h. Methanesulfonyl chloride (0.05 mL, 0.65 mmol,0.08 eq.) was added dropwise. After the addition, the mixture wasstirred 0.5 h. The solution was extracted with 1N HCl (2×100 mL) and 5%NaHCO₃ (100 mL). The organic phase was dried over MgSO₄, filtered, andconcentrated in vacuo to obtain a residue. The residue was dried underhigh vacuum at ambient temperature for 18 h to give the title compound:

R_(f) =0.27 (silica gel, ethyl acetate).

3.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethloxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (No.027F116)

2-[3,4-(Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate,(376 mg, 0.707 mmol) was dissolved in THF (8 mL) and4-phenyl-piperidine-4 carboxylic acid amide hydrochloride (170 mg, 0.707mmol, 1 eq.), potassium carbonate (200 mg, 1.45 mmol, 2 eq.), and water(2 mL), were added and the solution was heated at reflux for 16 h. Thesolution was concentrated in vacuo and the aqueous phase was extractedwith dichloromethane. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (40 g) with a gradient of ethyl acetate to6% methanol in dichloromethane to isolate the the title compound. Theresidue was dissolved in dichloromethane and added dropwise into asaturated ether/HCl solution. The slurry was concentrated in vacuo andthe residue was dried under high vacuum at 50° C. to give thehydrochloride salt of the title compound 321 mg (71%).

Analysis: calculated for C₃₄ H₃₉ Cl₂ N₃ O₅.HCl.0.5 H₂ O: C 62.93; H6.21; N 6.48. Found C 62.86; H 6.19; N 6.30.

3.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(7.87 mmol) and THF/H₂ O (3/1, 80 mL) were combined.4-Phenyl-piperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) wereadded. The mixture was heated to reflux for 72 h. The mixture wasconcentrated in vacuo. The aqueous residue was extracted withdichloromethane. The organic phase was extracted with H₂ O (50 mL). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuoto obtain a residue. The residue was purified by chromatography onsilica gel (350 g) eluting sequentially with ethyl acetate, 6% methanolin dichloromethane, and then 10% methanol in dichloromethane to give thetitle compound:

R_(f) =0.12 (silica gel, 6% methanol in dichloromethane).

Analysis: calculated for C₃₄ H₃₉ Cl₂ N₃ O₅.0.5 H₂ O C 62.93; H 6.21; N6.48; Found C 62.86; H 6.19; N 6.30.

3.3.2 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (240 mg, 0.5 mmol) and 3,4,5-trimethoxy-benzoicacid to give the title compound: R_(f) =0.43 (silica gel, 10%methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₄ H₄₀ Cl₂ N₃ O₄ calculated 624.2395.Found 624.2393.

EXAMPLE 3A

3.3A.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-ethyl-piperidine-4-carboxylicacid amide (4.33 g, 6.45 mmol) was dissolved in dichloromethane (20 mL)and treated with a solution of dichloromethane saturated with HCl(g) (20mL). The solution was allowed to stir for 1 h. The solution wasconcentrated in vacuo to obtain a residue. The residue was dried underhigh vacuum at 56° C. for 18 h to give the title compound:

mp=175°-185° C. (slow dec. to glass)

Analysis: calculated for C₃₄ H₄₀ Cl₃ N₃ O₅ C 60.32; H 5.95; N 6.21;Found C 60.09; H 6.32; N 6.11.

EXAMPLE 4 Synthesis of1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide

4.1 Synthesis of[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F103)

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine, (218 mg, 0.83mmol) was dissolved in dichloromethane at -78° C. and treated with4-methylmorpholine (0.19 mL, 1.73 mmol, 2 eq.) and 2-methoxybenzoylchloride (155 mg, 0.84 mmol, 1 eq.) in dichloromethane (3×1 mL). Thesolution was allowed to warm to 0° C. and stir for 4.5 hours. Thesolution was washed with 1N HCl and 5% sodium bicarbonate and theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel (30g) with a gradient of 50% ethyl acetate in hexane to 6% methanol indichloromethane to give 202 mg (60%) of the title compound.

4.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl-methanesulfonate(No.027F104)

3-(3,4-Dichloro-phenyl)-1-(2-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F103) (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL)and diisopropylethylamine (0.17 mL, 0.976 mmol, 2 eq.) andmethanesulfonyl chloride (0.050 mL, 0.646 mmol, 1.3 eq.) were addeddropwise at 0° C. The solution was allowed to stir for 30 minutes at 0°C. The solution was diluted with dichloromethane and washed with 1N HCland 5% sodium bicarbonate. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (25 g) with a gradient from 50% ethylacetate in hexane to 6% methanol in dichloromethane to give 210 mg (88%)of the title compound.

4.3 Synthesis of1-(2-[3-(3,4-dichloro-phenyl)-1-[2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide (No.027F104)

2-[3-(3,4-Dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl] ethylmethanesulfonate (No.027F104) (210 mg, 0.43 mmol), was dissolved in THF(4 mL) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(105 mg 0.44 mmol), sodium bicarbonate (75 mg, 0.89 mmol), and water (1mL), were added and the solution was heated at reflux for 22 hours. Thesolution was concentrated in vacuo and the aqueous phase was extractedwith dichloromethane. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (30 g) with a gradient from ethyl acetateto 10% methanol in dichloromethane to give 205 mg (80%) of the titlecompound.

Analysis: calculated for C₃₃ H₃₇ Cl₂ N₃ O₃.0.5 H₂ O C 65.47; H 6.16; N6.94. Found C 65.86; H 6.43; N 7.02.

EXAMPLE 5 Synthesis of1-(2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide

5.1 Synthesis of[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F130)

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (2 g, 7.695mmol) was dissolved in dichloromethane at -78° C. and treated with4-methylmorpholine (1.8 mL, 16.4 mmol, 2.1 eq.) and2,6-dimethoxy-benzoyl chloride (1.55 g, 7.73 mmol) in dichloromethane(20 mL). The solution was allowed to warm to 0° C. and stirred for 1.5hours. The solution was washed with 1N HCl and 5% sodium bicarbonate andthe organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel(200 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol indichloromethane to give 2.434 g (75%) of the title compound.

5.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(No.027F130)

3-(3,4-Dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(2.434 g, 5.74 mmol), was dissolved in dichloromethane (30 mL) andtreated with N,N-diisopropylethylamine (2.1 mL, 12.06 mmol, 2.1 eq.) andmethanesulfonyl chloride (0.53 mL, 6.85 mmol, 1.2 eq.) at 0° C. for 1hour. The solution was washed with 1N HCl, and 5% sodium bicarbonate.The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel(150 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol indichloromethane to give 2.8041 g (97%) of the title compound.

5.3 Synthesis of1-(2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide (No.027F131)

2-[3-(3,4-Dichloro-phenyl)-1-(2,6-dimethoxybenzoyl)-pyrrolidin-3-yl]ethyl methanesulfonate (2.0 g, 3.98 mmol) was dissolved in THF (40 mL)and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (1 g, 4.16mmol), water (10 mL), and potassium carbonate (1.2 g, 8.68 mmol) wereadded and the solution was heated at reflux for 18 hours. The solutionwas concentrated in vacuo. The aqueous phase was extracted withdichloromethane three times and the organic phase was washed with water,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was chromatographed on silica gel (150 g) with a gradient fromethyl acetate to 10% methanol in dichloromethane to give 1.2515 g (52%)of a residue. CI/MS (m/e) 610 (M+H) for C₃₃ H₃₇ Cl₂ N₃ O₄.

The residue was dissolved in dichloromethane (5 mL) and filtereddropwise into a saturated ether/HCl solution. The slurry wasconcentrated in vacuo and the residue was dried under high vacuum at 55°C. to give 1.04 g (78%) of the title compound.

Analysis: calculated for C₃₃ H₃₇ Cl₂ N₃ O₄.HCl C 61.26; H 5.92; N 6.49.Found C 61.19; H 6.22; N 6.57.

EXAMPLE 5A Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

5A.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

1-[2-[3-(3,4-Dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (1.8 mmol) was dissolved in dichloromethane (20 mL) andtreated with a solution of dichloromethane saturated with HCl(g) (20mL). The solution was allowed to stir for 1 h. The solution wasconcentrated in vacuo to obtain a residue. The residue was dried underhigh vacuum at 56° C. for 18 h to give the title compound.

Analysis: calculated for C₃₃ H₃₈ Cl₃ N₃ O₄ C 61.26; H 5.92; N 6.49;Found C 61.18; H 6.22; N 6.57.

EXAMPLE 6 Synthesis of2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-pentanedioicacid dimethyl ester

6.1 Synthesis of1-tert-butyloxycarbonyl-4-phenyl-piperidine-4-carboxylic acid methylester (No.03F169)

1-tert-Butyloxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (0.9162 g,3 mmol) was allowed to react with methyl iodide (1.87 mL, 30 mmol, 10eq.) in the presence of N,N-diisopropylethylamine (2.61 mL, 15 mmol, 5eq.) in acetonitrile (30 mL) at 20° C. for 16 hours. The solution wasdiluted with ethyl acetate and washed with 1N HCl, saturated sodiumbicarbonate and saturated sodium chloride. The organic phase was driedover magnesium sulfate and the solvent was concentrated in vacuo to give0.935 g (98%) of the title compound.

6.2 Synthesis of 4-phenyl-piperidine-4-acid methyl ester hydrochloride(No.03F170)

1-tert-Butyloxycarbonyl-4-phenyl-piperidine-4-acid methyl ester (0.9345g, 2.93 mmol) was allowed to stir in 4N HCl in dioxane (10 mL) at 20° C.for 45 minutes. The solution was concentrated in vacuo and the residuewas dried in vacuo to give 0.7143 g (95%) of the title compound.

6.3 Synthesis of1-[2-[1-benzoyl-3-(3,4-dichloro-phenyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl ester (003F171)

4-Phenyl-piperidine-4-carboxylic acid methyl ester hydrochloride (0.4143g, 1.62 mmol) and2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.7165 g, 1.62 mmol) were dissolved in THF/H₂ O (20 mL/4 mL) andtreated with sodium bicarbonate (0.2592 g, 3.24 mmol) at reflux for 16hours. The solution was diluted with ethyl acetate and the aqueous phasewas extracted with dichloromethane. The combined organic phases weredried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was chromatographed on silica gel with 1% methanol indichloromethane to give 0.2850 g (31%) of the title compound.

6.4 Synthesis of1-[2-[-1-benzoyl-3-(3,4-dichloro-phenyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (003F172)

1-[2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl ester (0.2850 g, 0.5 mmol) was dissolved in ethanol (10 mL)and treated with 1M sodium hydroxide (5 mL, 5 mmol) at 20° C. for 2hours. The aqueous phase was washed with ethyl acetate. The aqueousphase was acidified with 1N hydrochloric acid, and then extracted withethyl acetate. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo to give 0.117 g (43%) of the titlecompound.

6.5 Synthesis of2-[(2-[1-benzoyl-3-(3,4-dichloro-phenyl)pyrrolidin-3yl]-ethyl]-4-phenyl-piperidine-4-carbonyl)-amino]-pentanedioicacid dimethyl ester (003F175)

A mixture of1-[2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (49 mg, 0.11 mmol, 1.1 eq.), L-glutamic acid dimethyl esterhydrochloride (0.0260 g, 0.1 mmol), EDC (0.0236 g, 0.12 mmol, 1.2 eq.),HOBT (0.0180 g, 0.12 mmol, 1.2 eq.), and N,N-diisopropylethylamine (0.03mL, 0.12 mmol, 1.2 eq.) were dissolved in dichloromethane (2 mL) andstirred 16 hours at 20° C. The solution was diluted with ethyl acetateand washed with 1N hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel with 5% methanol in dichloromethane togive 63 mg (81%) of the title compound.

Analysis: calculated for C₃₈ H₄₃ Cl₂ N₃ O₆ C 64.40; H 6.11; N 5.93.Found C 64.07; H 6.28; N 5.87.

EXAMPLE 7 Synthesis of2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxyl)-amino]-3-hydroxybutyric acid methyl ester (003F176).

7.1 Synthesis of2-[(1-(2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxyl)-amino]-3-hydroxybutyricacid methyl ester (003F176).

1-[2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (61 mg, 0.1 mmol), L-threonine methyl ester hydrochloride (0.0187g, 0.11 mmol, 1.1 eq.), EDC (0.0216 g, 0.11 mmol, 1.1 eq.), HOBT (0.0165g, 0.11 mmol, 1.1 eq.), and N,N-diisopropylethylamine (0.0257 mL, 0.11mmol, 1.1 eq.) were dissolved in dichloromethane (2 mL) and stirred 16hours at 20° C. The solution was diluted with ethyl acetate and washedwith 1N hydrochloric acid, saturated sodium bicarbonate, and saturatedsodium chloride. The organic phase was dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was chromatographed onsilica gel with 5% methanol in dichloromethane to give 34.2 mg (51%) ofthe title compound.

Analysis: calculated for C₃₆ H₄₁ Cl₂ N₃ O₅ C 64.86; H 6.20; N 6.30.Found C 64.62; H 6.49; N 6.42.

EXAMPLE 8 Synthesis of1-[2-[1-benzoyl-3-naphthylen-2-yl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidin-4-carboxylicacid amide.

8.1 Synthesis of 3-cyano-3-(2-naphthyl)-pentanedioic acid diethyl ester(03F106).

2-Naphthylacetonitrile (1.6721 g, 10 mmol) in THF (80 mL) at -78° C. wastreated with sodium bis-(trimethylsilyl)amide (20 mL, 1M in THF; 20mmol, 2 eq.). The solution was allowed to warm to 20° C. and stir for 2hours. The solution was cooled to -78° C. and ethyl bromoacetate (2.2mL, 20 mmol, 2 eq.) was added. The solution was allowed to warm to 20°C. and stir 16 hours. The solution was diluted with dichloromethane andwashed with water. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel with a gradient from 5% ethyl acetate in hexane to 20% ethylacetate in hexane to give 3.2124 g (95%) of the title compound.

8.2 Synthesis of [3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl]-acetic acidethyl ester (003F115).

3-Cyano-3-(2-naphthyl-pentanedioic acid diethyl ester (3.2124 g, 9.47mmol) was hydrogenated at 40 psi over Raney nickel (10 g) in ethanol (60mL) and ammonium hydroxide (25 mL) for 8 hours. The slurry was filteredand the filtrate was concentrated in vacuo. The residue waschromatographed on silica gel with a gradient from 30% ethyl acetate inhexane to 2% methanol in dichloromethane to give 1.0337 g (68%) of thetitle compound.

8.3 Synthesis of 3-(2-naphthalen-2-yl-pyrrolidin-3-yl-ethanol (003F122).

3-(2-Naphthalen-2-yl-5-oxo-pyrrolidin-3-yl)-acetic acid ethyl ester(1.2636 g, 4.25 mmol) in THF (20 mL) was added slowly to a solution ofLAH (0.6451 g, 17 mmol) in THF (20 mL) at room temperature. The slurrywas heated at reflux for 12 hours and additional LAH (0.3225 g,8.5.mmol) was added and then heated at reflux for an additional 8 hours.The slurry was treated dropwise with 0.98 mL of H₂ O, 0.98 mL of 15%sodium hydroxide, and 2.94 mL of H₂ O. The slurry was dried overmagnesium sulfate, filtered, and concentrated in vacuo to give 0.9145 g(89%) of the title compound.

8.4 Synthesis of 1-benzoyl-3-(2-hydroxyethyl)-3-(2-naphthyl)pyrrolidine(003F129)

3-(2-Naphthylen-2-yl-pyrrolidin-3-yl)-ethanol (003F122) (0.1207 g, 0.5mmol crude) was dissolved in dichloromethane and cooled to 0° C. Benzoylchloride (0.06 mL, 0.5 mmol, 1 eq.) and N,N-diisopropylethylamine (0.09mL, 0.5 mmol, 1 eq.) were added at 0° C. The solution was stirred at 0°C. for 4 hours and then diluted with ethyl acetate and washed with 1NHCl, saturated sodium bicarbonate, and saturated sodium chloride. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gelwith a gradient from 35% ethyl acetate in hexane to 4% methanol in CHCl₃to give 0.1061 g (61%) of the title compound.

8.5 Synthesis of2-[1-benzoyl-3-napthylen-2-yl-pyrrolidin-3-yl]-ethyl-methanesulfonate(003F134).

1-Benzoyl-3-(2-hydroxyethyl)-3-(2-naphthyl)pyrrolidine 003F129 (1.0501g, 3.04 mmol) in dichloromethane (30 mL) was cooled to 0° C., andtreated with N,N-diisopropylethylamine (0.93 mL, 3.95 mmol, 1.3 eq.) andmethanesulfonyl chloride (0.28 mL, 3.65 mmol, 1.2 eq.). The solution wasallowed to stir at 0° C. for 2 hours and more N,N-diisopropylethylamine(0.93 mL, 3.95 mmol, 1.3 eq.) and methanesulfonyl chloride (0.28 mL,3.65 mmol, 1.3 eq.) was added and the solution was allowed to stir foran additional 2 hours at 0° C. The solution was concentrated in vacuoand the residue was chromatographed on silica gel with 1% methanol indichloromethane to give 1.297 g (97%) of the title compound.

8.6 Synthesis of1-[2-[1-benzoyl-3-naphthylen-2-yl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (003F136)

2-[1-Benzoyl-3-napthylen-2-yl-pyrrolidin-3-yl]-ethyl methanesulfonate(003F134), (1.1363 g, 2.58 mmol), 4-phenyl-piperidine-4-carboxylic acidamide hydrochloride (0.6846 g, 2.84 mmol, 1.1 eq.), sodium bicarbonate(0.4335 g, 5.16 mmol, 2 eq.) in THF/H₂ O (25 mL/5 mL) was heated atreflux for 16 hours. The solution was concentrated in vacuo and theaqueous phase was extracted with dichloromethane. The organic phase waswashed with water, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gelwith a gradient from 3% methanol in dichloromethane to 5% methanol indichloromethane to give 0.8325 g (61%) of the title compound.

Analysis: calculated for C₃₅ H₃₇ N₃ O₂.H₂ O C 76.48; H 7.15; N 7.64.Found C 76.10; H 7.13; N 7.71.

EXAMPLE 9 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-one(027F145).

9.1 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(2,6-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-one(027F145).

2-[1-(2,6-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethylmethanesulfonate (200 mg, 0.398 mmol), and1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (100 mg, 0.432 mmol) weredissolved in THF/H₂ O (4 mL/1 mL) and treated with potassium carbonate(110 mg, 0.796 mmol, 2 eq.) at reflux for 22 hours. The solution wasconcentrated in vacuo and the aqueous phase was extracted (3×) withdichloromethane. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel (40 g) with a gradient from ethyl acetate to 10% methanol indichloromethane to give 130 mg (51%) of the title compound.

Exact mass (Cl): calculated for C₃₄ H₃₉ Cl₂ N₄ O₄ (M+H): 637.2348. Found637.2322.

EXAMPLE 10 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-benzoyl-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-one(027F60).

10.1 Synthesis of2-[1-benzoyl-3-)3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(027F60a).

1-Benzoyl-3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl) pyrrolidine (350 mg,0.962 mmol) was dissolved in dichloromethane (6 mL) at 0° C. andN,N-diisopropylethylamine (0.25 mL, 1.44 mmol, 1.5 eq.) andmethanesulfonyl chloride (0.090 mL, 1.16 mmol, 1.2 eq.) were added. Thesolution was allowed to stir for 2 hours. Methanesulfonyl chloride(0.015 mL, 0.19 mmol, 0.2 eq.) was added and the solution was allowed tostir an additional 30 minutes. The solution was diluted withdichloromethane and washed with 1N HCl and 5% sodium bicarbonate. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel(40g) with 2% methanol in dichloromethane to give 427 mg (99%) of thetitle compound.

10.2 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-4-one(027F60b).

2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(427 mg, 0.962 mmol) (027F60a), was dissolved in THF (6 mL) and1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (270 mg, 1.167 mmol, 1.2eq.), water (1.5 mL) and sodium bicarbonate (150 mg, 1.79 mmol, 1.86eq.) were added. The slurry has heated at reflux for 21 hours and thenconcentrated in vacuo. The aqueous phase was extracted withdichloromethane. The organic phase was washed with water, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (50 g) with a gradient from ethyl acetateto 10% methanol in dichloromethane to give 354 mg (64%).

Analysis: calculated for C₃₂ H₃₄ Cl₂ N₄ O₂.H₂ O C 64.60; H 6.10; N 9.42.Found C 64.79; H 6.04; N 9.27.

EXAMPLE 11 Synthesis of1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

11.1 Synthesis of2-(3,4-dichloro-phenyl)-4-(tetrahydro-pyran-2-yl-oxy)-butyronitrile

Sodium hydride (1.42 g, 59.2 mmol) in THF (25 mL) was treated with3,4-dichlorophenylacetonitrile (10 g, 53.75 mmol) in THF (60 mL) at -78°C. and then the slurry was allowed to warm to 20° C. and stir for 2.5hours. The solution was cooled to 0° C. and2-(2-bromo-ethoxy)-tetrahydro-pyran in THF (25 mL) was added dropwise.The solution was allowed to warm to 20° C. and stir for 16 hours. Thesolution was poured into saturated ammonium chloride and extracted withdiethyl ether. The organic phase was extracted with water and brine andthe organic phase was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was chromatographed on silica gel(500 g) with a gradient from 5% ethyl acetate in hexane to 20% ethylacetate in hexane to give 12.134 g (72%) of the title compound.

11.2 Synthesis of 3cyano-3-(3,4-dichloro-phenyl)-5-(tetrahydro-pyran-2-yloxy) pentanoicacid ethyl

ester (027F32-33).

2-(3,4-dichloro-phenyl)-4-(tetrahydro-pyran-2yloxy)-butyronitrile(10.8669 g, 34.62 mmol) was dissolved in THF (20 mL) at -78° C. andtreated dropwise with LDA (27.2 mL, 40.8 mmol, 1.18 eq.) over 30minutes. The solution was allowed to stir for 1.25 hour. Ethylbromoacetate (4.2 mL, 37.87 mmol, 1.09 eq.) was added dropwise at -78°C. and the solution was allowed to warm to 20° C. and stir for 4 hours.The solution was partitioned between ammonium chloride and diethylether. The organic solution was extracted with water and brine and theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel(400 g) with a gradient from 20% ethyl acetate in hexane to 30% ethylacetate in hexane to give 9.6243 g (69.5%) of the title compound.

11.3 Synthesis of4-(3,4-dichloro-phenyl)-4-(tetrahydro-pyran-2-yloxy)ethyl)-pyrrolidin-2-one(027F34).

3-Cyano-3-(3,4-dichloro-phenyl)-5-(tetrahydro-pyran-2-yloxy) pentanoicacid ethyl ester (027F32a) (9.5 g, 23.76 mmol) was dissolved inethanol/ammonium hydroxide (190 mL/38 mL) and hydrogenated in a Parrshaker at 45 psi for 7 hours over Raney nickel (30 g). The slurry wasfiltered and the filtrate was concentrated in vacuo. The residue waschromatographed on silica gel (30 g) with a gradient from 30% ethylacetate in hexane to 10% methanol in dichloromethane to give 6.85 g(81%) of the title compound.

11.4 Synthesis of1-benzyl-4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one(027F43).

4-(3,4-Dichloro-phenyl)-4-(tetrahydro-pyran-2-yloxy)ethyl)-pyrrolidin-2-one(027F34) (1 g, 2.79 mmol) was dissolved in THF (10 mL) and treated withsodium hydride (80 mg, 1.2 eq.) and benzyl bromide (0.7 mL, 5.89 mmol)at 20° C. The solution was allowed to stir 7.5 hours. The slurry waspartitioned between diethyl ether and ammonium chloride and the solutionwas washed with water and brine. The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel (100 g) with 50% ethyl acetate in hexaneto give 1.194 g (99%) of the title compound.

11.5 Synthesis of1-benzyl-4-(3,4dichloro-phenyl)-4-(2-hydroxy-ethyl-pyrrolidin-2-one(027F44a).

1-Benzyl-4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one(027F43) (1.0 g, 2.79 mmol) was dissolved in methanol (6 mL) and treatedwith p-toluenesulfonic acid (200 mg) at room temperature for 5 hours.The solution was concentrated in vacuo and the residue was dissolved indichloromethane and washed with 5% sodium bicarbonate and water. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on silica gel (100 g)with a gradient from 50% ethyl acetate in hexane to 10% methanol indichloromethane to give 779 mg (77%) of the title compound.

11.6 Synthesis of2-[4-benzyl-3-3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethylmethanesulfonate (027F44b).

1-Benzyl-4-(3,4-dichloro-phenyl)-4-(2-hydroxy-ethyl-pyrrolidin-2-one(027F44a) (779 mg, 2.14 mmol) was dissolved in dichloromethane (10 mL)and treated with N,N-diisopropylethylamine (0.5 mL; 2.87 mmol, 1.34 eq.)and methanesulfonyl chloride (0.2 mL, 2.58 mmol, 1.2 eq.) at 0° C. for 2hours. The solution was washed with 1N HCl, 5% sodium bicarbonate, andwater, and the organic phase was dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was chromatographed on silica gel(100 g) with a gradient from 50% ethyl acetate in hexane to ethylacetate to give 815 mg (86%) of the title compound.

11.7 Synthesis of1-[2-[1-benzyl-3-(3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (027F44c).

2-[4-Benzyl-3-3,4-dichloro-phenyl)-5-oxo-pyrrolidin-3-yl]-ethylmethanesulfonate (027F44b) (815 mg, 1.84 mmol) was dissolved inTHF/water (15 ml/4 ml) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (520 mg, 2.16 mmol, 1.17 eq.) and sodium bicarbonate (320mg, 3.8 mmol, 2.1 eq) were added. The solution was heated at reflux for16 hours. The solvents were concentrated in vacuo. The aqueous phase wasextracted with dichloromethane and the organic phase was washed withwater. The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel(100 g) with 10% methanol in dichloromethane to give 389 mg (38%) of thetitle compound.

Exact mass (Cl): calculated for C₃₁ H₃₄ Cl₂ N₃ O₂ (M+H) 550.2028. Found550.2018.

EXAMPLE 12 Synthesis of1-[1-benzyl-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (003F112-113)

12.1 .Synthesis of2-(2-naphthyl)-4-(tetrahydro-pyran-2-yloxy)-butyronitrile (003F112)

2-Napthylacetonitrile (3.3442 g, 20 mmol) in THF (50 mL) was added tosodium hydride (0.528 g, 22 mmol, 1.1 eq.) in THF (50 mL) at -78° C.under nitrogen. The slurry was allowed to warm to 20° C. and stir for 2hours. The slurry was cooled to 0° C. and2-(2-bromo-ethoxy)-tetrahydro-pyran (4.1786 g, 20 mmol, 1 eq.) wasadded. The solution was allowed to stir at 20° C. for 16 hours and thendiluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was chromatographed on silica gel with a gradient from 5%ethyl acetate in hexane to ethyl acetate to give 1.9774 g (66%) of thetitle compound.

12.2 Synthesis of3-cyano-3-naphthalen-2-yl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acidethyl ester (003F143).

2-(2-Napthyl)-4-(tetrahydro-pyran-2-yloxy)-butyronitrile (003F112) (1.9g, 6.45 mmol) in THF (60 mL) was cooled to -78° C. and treated dropwisewith LDA (1.5M, 5.2 mL, 7.75 mmol, 1.2 eq.) and allowed to stir for 1hour. Ethyl bromoacetate (0.86 mL, 7.75 mmol, 1.2 eq.) was addeddropwise and the solution was allowed to warm to 20° C. and stir for 18hours. The solution was partitioned between saturated aqueous ammoniumchloride solution and ethyl acetate. The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica gel with a gradient from 20% ethyl acetate inhexane to 50% ethyl acetate in hexane to give 1.474 g (39%) of the titlecompound.

12.3 Synthesis of4-naphthalen-2-yl-4-[2(tetrahydro-pyran-2-yloxy)-ethyl]-pyrrolidin-2-one(003F144).

3-Cyano-3-naphthalen-2-yl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acidethyl ester (003F143) (1.6154 g, 4.23 mmol) was hydrogenated at 40 psiover Raney nickel (10 g) for 16 hours. The slurry was filtered and thefiltrate was concentrated in vacuo. The residue was chromatographed onsilica gel with a gradient from 50% ethyl acetate in hexane to 5%methanol in dichloromethane to give 0.8305 g (83%) of the titlecompound.

12.4 Synthesis of1-benzyl-4-naphthalen-2-yl-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]pyrrolidin-2-one(003F145).

Sodium hydride (0.07 g, 2.94 mmol, 1.25 eq.) was added slowly to asolution of4-naphthalen-2-yl-4-[2(tetrahydro-pyran-2-yloxy)-ethyl]-pyrrolidin-2-one(003F144) (0.81 g, 2.39 mmol). The solution was treated with benzylbromide (0.6 mL, 4.9 mmol, 2 eq.) at 20° C. for 7 hours. The solutionwas partitioned between saturated aqueous ammonium chloride and ethylacetate. The organic phase was dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was chromatographed on silica gelwith 50% ethyl acetate in hexane to give 1.1620 g (92%) of the titlecompound.

12.5 Synthesis of 1-benzyl-4-2-hydroxy-ethyl-4-napthalene-2-1yl-pyrrolidin-2-one (003F146).

1-Benzyl-4-naphthalen-2-yl-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]pyrrolidin-2-one(003F145) (1.1620 g, 2.71 mmol) was dissolved in methanol (2.7 mL) andtreated with p-toluenesulfonic acid (0.0515 g, 0.27 mmol, 0.1 eq.). Thesolution was allowed to stir at 20° C. for 4 hours. The residue waschromatographed on silica gel with a gradient from 50% ethyl acetate inhexane to 5% methanol in dichloromethane to give the 0.6161 g (66%) ofthe title compound.

12.6 Synthesis of 2-[1-benzyl-3-naphthalene-2-yl-5-oxo-pyrrolidin-3-yl)ethyl methanesulfonate (003F147).

1-Benzyl-4-(2-hydroxyethyl)-4-napthalene-2-yl-pyrrolidin-2-one (003F146)(0.6161 g, 1.78 mmol) in dichloromethane (17 mL) at 0° C. was treatedwith N,N-diisopropylethylamine (0.84 mL, 3.56 mmol, 2 eq.) andmethanesulfonyl chloride (0.27 mL, 3.56 mmol, 2 eq.). The solution wasallowed to stir at 0° C. for 2 hours. The solution was concentrated andthe residue was chromatographed on silica gel with 1% methanol indichloromethane to give 0.7219 g (95%) of the title compound.

12.7 Synthesis of1-[2-(1-benzyl)-3-naphthalen-2-yl-5-oxo-pyrrolidin-3-yl)-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (003F148).

2-[1-Benzyl-3-naphthalene-2-yl-5-oxo-pyrrolidin-3-yl)-ethyl-methanesulfonate(003F147) (0.5061 g, 1.19 mmol) was dissolved in THF/H₂ O (12 mL/12 mL)and treated with 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (0.3155 g, 1.31 mmol, 1.1 eq.) and sodium bicarbonate(0.1999 g, 2.38 mmol) at reflux for 18 hours. The aqueous phase wasextracted with dichloromethane and the organic phases were dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waschromatographed on silica gel with 5% methanol in dichloromethane togive 0.5060 g (80%) of the title compound.

Exact mass (CI): calculated for C₃₅ H₃₈ N₃ O₂ (M+H): 532.2964. Found532.2981.

EXAMPLE 13 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl]-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

13.1 Synthesis of[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(No.027F099)

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (200 mg, 0.76mmol) was dissolved in dichloromethane (5 mL) at -78° C. and treatedwith 4-methylmorpholine (0.17 mL, 1.55 mmol, 2 eq.) and2-methoxy-benzoyl chloride (0.11 mL, 0.74 mmol). The solution wasallowed to warm to 0° C. and stir for 1 hour. The solution was washedwith 1N HCl and 5% sodium bicarbonate and the organic phase was driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas chromatographed on silica gel (30 g) with a gradient of 50% ethylacetate in hexane to 3% methanol in dichloromethane to give 268 mg (90%)of the title compound.

13.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(No.027F100)

[3-(3,4-Dichloro-phenyl)-1-(2-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(268 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL) and treatedwith N,N-diisopropylethylamine (0.24 mL, 1.38 mmol, 2 eq.) andmethanesulfonyl chloride (65 mL, 0.84 mmol, 1.2 eq.) at 0° C. for 1hour. The solution was washed with 1N HCl, and 5% sodium bicarbonate.The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on silica gel (30g) with ethyl acetate to give 323 mg (99%) of the title compound.

13.3 Synthesis of1-(2-[3-(3,4-dichloro-phenyl)-1-(2-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylicacid amide (No. 027F131)

2-[3-(3,4-Dichloro-phenyl)-1-(2-methoxybenzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(323 mg, 0.68 mmol) was dissolved in THF (4 mL) and4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (165 mg, 0.69mmol), water (1 mL), and sodium bicarbonate (105 mg, 1.25 mmol) wereadded and the solution was heated at reflux for 21 hours. The solutionwas concentrated in vacuo. The aqueous phase was extracted withdichloromethane (3×) and the organic phase was washed with water, driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas chromatographed on silica gel (30 g) with a gradient from ethylacetate to 6% methanol in dichloromethane to give 280 mg (73%) of thetitle compound.

Exact mass (Cl): calculated for C₃₂ H₃₆ Cl₂ N₃ O₃ (M+H): 580.2134. Found580.2143.

EXAMPLE 20 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-4-phenyl-piperidine-4-carboxylicacid amide

20.2 Synthesis ofethyl-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-acetate

2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(4.5 g, 9.9 mmol) was dissolved in dichloromethane/pyridine (70 mL,6/1). The solution was treated with acetic anhydride (1.04 mL, 11.02mmol, 1.1 eq.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.04 eq.).The solution was allowed to stir for 2 h at ambient temperature. Theorganics were concentrated in vacuo and the residue was dissolved inethyl acetate and washed with 1N HCl (2×200 mL), 5% NaHCO₃ (100 mL),brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo.The residue was chromatographed on silica gel (300 g) with ethyl acetateto afford the title compound:

R_(f) =0.38 (silica gel, ethyl acetate).

Analysis: calculated for C₂₄ H₂₇ Cl₂ NO₆ C 58.07; H 5.48; N 2.82; FoundC 57.67; H 5.46; N 2.84.

20.3 Synthesis of(+)-ethyl-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-acetate

Ethyl-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-acetate(6.6 g, 13.31 mmol) was dissolved in dichloromethane (100 mL) andtreated with silica gel (32 g). The slurry was concentrated in vacuo andthe residue was added to a 2 L three necked round-bottomed flask. Theresidue was suspended in phosphate buffer (800 mL, 0.1M, pH=7.5, thebuffer was prepared with 11.5 g H₃ PO₄ (85%) diluted to 1 L withdeionized H₂ O and then adjusting the pH with solid KOH pellets to 7.5).The slurry was treated with Lipase (13 g, EC 3.1.1.3, Type VII, fromCandida cylindracea). The slurry was allowed to stir at ambienttemperature for 84 h. The reaction was monitored by HPLC on a CHIRALPAKAD 25 cm×0.46 cm column eluting with pentane/ethanol/methanol (80/15/5)with a flow rate of 1.0 mL/minute. An aliquot (50 mL) was extracted withethyl acetate (1 mL) in a centrifuge tube. The solution was centrifugedfor 10 minutes at 14000 cm⁻¹. The supernatant was removed andconcentrated under a nitrogen stream. The residue was dissolved indichloromethane (ca. 1 mL) and 5 mL was injected on the column foranalysis. When the enantiomeric excess (ee) was satisfactory (>95% ee)for the (+) acetate the reaction was filtered. The filtrate wasextracted with dichloromethane (8×500 mL). The solids were rinsed withdichloromethane (8×500 mL, the same portion was then used to extract thefiltrate). The solids were placed in a chromatography column and elutedwith 6% methanol in dichloromethane until all the alcohol and acetatewas eluted. The combined organics were concentrated in vacuo, dissolvedin dichloromethane, dried over MgSO₄, filtered and concentrated in vacuoto give a residue. The residue was chromatographed on silica gel (400g), eluting with ethyl acetate until the acetate was off and theneluting with 6% methanol in dichloromethane until the alcohols were offto give the title compound:

R_(f) =0.38 (silica gel, ethyl acetate).

Analysis: calculated for C₂₄ H₂₇ Cl₂ NO₆.0.5 H₂ O C 57.14; H 5.59; N2.78; Found C 57.37; H 5.45; N 2.87.

HPLC determination of enantiomeric excess was 99%. [α]²⁰=+36.4°(c=0.894, CHCl₃).

20.4 Synthesis of(+)-2-[3-(3,4-dichloro-phenyl)-1-3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

(+)-Ethyl-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-acetate(670 mg, 1.351 mmol, 99% ee) was dissolved in methanol (15 mL) andtreated with LiOH (4.2 mL, 1N, 3.1 eq.) at ambient temperature for 3.5h. The organics were concentrated in vacuo. The residue was dissolved indichloromethane and washed with 1N HCl (50 mL), 5% NaHCO₃ (50 mL), driedover MgSO₄, filtered, and concentrated in vacuo to obtain a residue. Theresidue was dried under high vacuum for 18 h to give the title compound:

R_(f) =0.11 (silica gel, ethyl acetate).

20.4.1 Resolution of (+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (R,R)-di-p-anisoyltartaric acid salt

Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (1.0 g,38.5 mmol) and butanone. Add a solution of (R, R)-di-p-anisoyltartaricacid (1.6 g, 38.0 mmol) in butanone (80 mL). Heat to reflux. After 15minutes, cool to ambient temperature and then cool further in anice-salt bath. Filter the solid that forms and rinse with butanone.Recrystallize the solid from water/methanol to give the title compound:mp; 201°-204° C. (dec). Analysis on HPLC, on an analytical sample of thefree amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cmcolumn eluting with pentane/methanol/triethylamine (90/10/0.1) with aflow rate of 1.0 mL/minute indicates an enantiomeric excess of 96%, (96%ee), retention time of the (+)-isomer 11.2 minutes, retention time ofthe (-)-isomer 14.5 minutes.

20.4.2 Resolution of(+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (R,R)-di-p-anisoyltartaric acid salt

Combine (R, R)-di-p-anisoyltartaric acid (354.1 g, 846 mmol) and aqueous12M hydrochloric acid solution (70.5 mL, 846 mmol) in water/methanol(4.4 L)/(4.4 L). Heat to reflux. Add dropwise over 45 minutes, asolution of 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (440g, 1693 mmol) in methanol (3 L). After 20 minutes, slowly cool toambient temperature. Filter the solid that forms and rinse with water togive the title compound: mp; 201°-204° C. (dec). Analysis by HPLC, asdescribed in Example 20.4.1 indicates an enantiomeric excess of 97.5%,(97.5% ee).

20.4.3 Synthesis of(+)-1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine

Combine (+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15mL, acetonitrile (6 mL), water, (6 mL) and sodium bicarbonate (0.09 g,1.03 mmol). Cool to 0° C. in an ice-salt bath. Add trimethoxy-benzoylchloride (0.048 g, 0.21 mmol). After 30 minutes, warm to ambienttemperature. After 30 minutes at ambient temperature, partition thereaction mixture between ethyl acetate and saturated aqueous sodiumchloride solution. Extract the organic layer with 1M hydrochloric acidsolution, then saturated aqueous sodium bicarbonate solution. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give thetitle compound: R_(f) =0.11 (silica gel, ethyl acetate).

20.4.4 Synthesis of(+)-1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine

Combine (+)-3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (772.7 g, 1140 mmol) and acetone (5L). Cool in to 0°-10° C. and add aqueous sodium hydroxide solution (46g, 1105 mmol, in 5 L of water). Add sodium bicarbonate (479 g, 5700mmol). While maintaining the temperature at 0°-10° C., add dropwise over30 minutes, trimethoxy-benzoyl chloride (262.9 g, 1140 mmol). After3.hours, add ethyl acetate (5L) and allow to warm to ambienttemperature. Separate the layers and extract the aqueous layer 3 timeswith ethyl acetate. Combine the organic layers and extract 1M sodiumhydroxide solution, 1M hydrochloric acid solution, and then saturatedaqueous sodium bicarbonate solution. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give a residue. Treat the residue withdichloromethane and evaporate in vacuo the title compound: R_(f) =0.36(silica gel, 6% methanol/dichloromethane).

20.5 Synthesis of(+)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using(+)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(1.351 mmol) and methanesulfonyl chloride (0.14 mL, 1.81 mmol, 1.34 eq.)to obtain a residue. The residue was dried under high vacuum for 18 h togive the title compound:

R_(f) =0.27 (silica gel, ethyl acetate).

20.6 Synthesis of 4-phenyl-piperidine-4-carboxylic acid hydrochloride

4-Cyano-4-phenylpiperidine hydrochloride (20.0 g, 89.8 mmol) and KOH(1.2 L, 3N, 3.6 mol, 40 eq.) were combined and heated at reflux for 15h. The solution was cooled in an ice bath and treated dropwise withconc. HCl until the pH=2. The white precipitate was collected and driedunder high vacuum at 56° C. for 15 h to give the title compound:

R_(f) =0.2 (silica gel, 85:10:5, chloroform:methanol:acetic acid).

Analysis: calculated for C₁₂ H₃₆ ClNO₂ C 59.63; H 6.67; N 5.79; Found C58.19; H 6.52; N 5.72.

20.7 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid

4-Phenyl-piperidine-4-carboxylic acid hydrochloride (2.42 g, 10 mmol)was combined with di-tert-butyl dicarbonate (2.4 g, 11 mmol) in DMF (100mL). N,N-diisopropylethylamine (1.91 mL, 11 mmol) was added to themixture and the mixture was allowed to stir at ambient temperature for30 h. The mixture was diluted with ethyl acetate and extracted with 1NHCl. The organic phase was extracted with 1N NaOH (2×200 mL). Theaqueous phase was cooled in an ice bath and treated with 1N HCl to pH=2.The aqueous phase was extracted with ethyl acetate. The organic phasewas dried over MgSO₄, filtered, and concentrated in vacuo to give aresidue. The residue was dried under high vacuum to give the titlecompound:

R_(f) =0.48 (silica gel, 6% methanol in dichloromethane, stains brownwith ninhydrin).

Analysis: calculated for C₁₇ H₂₃ NO₄ C 66.86; H 7.59; N 4.59; Found C66.56; H 7.72; N 4.52.

20.8 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid amide

1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.22 g, 4mmol) was combined with THF (40 mL) and cooled to -10° C. Triethylamine(0.61 mL, 4.4 mmol, 1.1 eq.) and isobutylchloroformate (0.57 mL, 4.4mmol, 1.1 eq.) were added and the reaction was allowed to warm toambient temperature and stir 15 h. The slurry was filtered and thesolids were rinsed with THF. The filtrate was cooled to -10° C. andsparged with NH₃ (gas) for 0.5 h. The slurry was allowed to warm to 20°C. and stir for 15 h. The slurry was filtered and the filtrate wasdiluted with ethyl acetate and washed with saturated NaHCO₃ (3×). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuoto give a residue. The residue was recrystallized from diethyl ether togive the title compound:

R_(f) =0.48 (silica gel, 6% methanol in dichloromethane, stains bluewith ninhydrin).

Analysis: calculated for C₁₇ H₂₄ N₂ O₃ C 67.08; H 7.95; N 9.20; Found C66.99; H 8.00; N 9.14. HPLC analysis R_(t) =30.16 min. using a VydacC-18 column eluting with an acetonitrile:water (0.1% TFA) gradient(elution with CH₃ CN/H₂ O(0.1%TFA), flow rate=1.0 mL/min., 10% CH₃ CNfor 10 minutes, 30% CH₃ CN for 15 minutes, 40% CH₃ CN for 15 minutes,50% CH₃ CN for 10 minutes, and then 100% CH₃ CN).

20.9 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid amide

1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.22 g, 4mmol) was combined with dichloromethane (40 mL).N,N-diisopropylethylamine (0.77 mL, 4.4 mmol, 1.1 eq.),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(0.8435 g, 4.4 mmol, 1.1 eq.), and 1-hydroxybenzotriazole hydrate (HOBT)(0.5946 g, 4.4 mmol, 1.1 eq.) were added. The mixture was allowed tostir at ambient temperature for 15 h. The solution was sparged with NH₃(gas) for 0.5 h and then allowed to stir at ambient temperature for 15h. The mixture was filtered and the filtrate was concentrated in vacuoto give a residue. The residue was dissolved in ethyl acetate andextracted with saturated NaHCO₃ (6×). The organic phase was dried overMgSO₄, filtered, and concentrated in vacuo to give a residue. Theresidue was recrystallized from diethyl ether to give the titlecompound:

R_(f) =0.48 (silica gel, 6% methanol in dichloromethane, stains bluewith ninhydrin).

20.10 Synthesis of 4-phenyl-piperidine-4-carboxylic acidamide-hydrochloride

1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid amide (0.95g, 3.12 mmol) was combined with HCl in dioxane (10 mL, 4N, 40 mmol, 13eq.) at ambient temperature for 1 h. The solvent was concentrated invacuo and ethyl acetate was added. The slurry was filtered and driedunder high vacuum for 48 h to give the title compound:

HPLC analysis R_(t) =5.56 min. using a C-18 column eluting with aacetonitrile:water (0.1% TFA), flow rate=1.0 mL/min., gradient (elutionwith CH₃ CN/H₂ O(0.1%TFA) 10% CH₃ CN for 10 minutes, 30% CH₃ CN for 15minutes, 40% CH₃ CN for 15 minutes, 50% CH₃ CN for 10 minutes, and then100% CH₃ CN).

Analysis: calculated for C₁₂ H₁₇ ClN₂ O C 59.87; H 7.12; N 11.64; FoundC 59.82; H 7.00; N 11.52.

20.11 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using(+)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(1.351 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (480 mg, 1.99 mmol, 1.5 eq.) to obtain a residue. Theresidue was chromatographed on silica gel (70 g) packed with ethylacetate, loaded with ethyl acetate, and eluted with ethyl acetate, 6%methanol in dichloromethane, and then 10% methanol in dichloromethane togive the title compound:

HPLC determination of enantiomeric excess was 96.8%.

R_(t) =13 minutes (with analytical column using a CHIRALPAK AD chiralHPLC column (25 cm×0.46 cm) with 15% methanol in pentane and a flow rateof 1.0 mL/minute.

20A.1 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

(+)-1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (1.17 g, 96.8% ee, 1.828 mmol) was dissolved indichloromethane (20 mL) and treated with a solution of dichloromethanesaturated with HCl (gas) (20 mL). The solution was allowed to stir for 1h. The solution was concentrated in vacuo to obtain a residue. Theresidue was dried under high vacuum at 56° C. for 18 h to afford thetitle compound:

mp=173°-185° C. (slow dec. to glass)

HPLC determination of enantiomeric excess was 96.8%.

R_(t) =13 minutes (with analytical column using a CHIRALPAK AD chiralHPLC column (25 cm×0.46 cm) with 15% methanol in pentane and a flow rateof 1.0 mL/minute.

Analysis: calculated for C₃₄ H₃₉ Cl₂ N₃ O₅. 0.77 H₂ O C 59.11; H 6.06; N6.08; Found C 59.50; H 6.11; N 6.07. [α]²⁰ =+13.2°(c=0.851, CH₃ OH).

20A.2 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

(+)-1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (54.0 g, 84.3 mmol) was dissolved in ethyl acetate (1 L) andthe solution was cooled to 0° C. The mixture was treated with a solutionof ethyl acetate ((167.7 g) containing HCl (gas) (7.8 g). When theaddition was complete the solid which had formed was collected byfiltration and rinsed with ethyl acetate and dried to give the titlecompound.

20B.1 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide maleate

(+)-1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (0.5 g, 0.78 mmol) was dissolved in ethanol (3 mL) and wastreated with a solution of maleic aid (0.10 g) in ethanol (2 mL). After10 minutes, the reaction mixture was triturated with diethyl ether (100mL) and the solid which formed was collected by filtration and dried togive the title compound.

Analysis: calculated for C₃₄ H₃₉ Cl₂ N₃ O₅.0.52 H₂ O .C₄ H₄ O₄ C 59.56;H 5.78; N 5.48; Found C 59.67; H 5.71; N 5.46.

20C.1 Synthesis of(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide citrate

(+)-1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (2.5 g) was dissolved in isopropanol (15 mL) and heated toreflux before the mixture was treated with a solution of citric aid(0.75 g) in isopropanol (13 mL). After 10 minutes, the reaction mixturewas cooled to ambient temperature and the solid which had formed wascollected by filtration and dried to give the title compound.

Analysis: calculated for C₃₄ H₃₉ Cl₂ N₃ O₅.1.0 H₂ O.C₆ H₈ O₇. 1.2 C₃ H₈O (isopropanol) C 56.75; H 6.42; N 4.54; Found C 56.66; H 6.34; N 4.47.

EXAMPLE 21 Chromatographic Resolution of(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Chromatographic Resolution of (+) and (-)-1-[2-[3-(3,4-Dichloro-andphenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

A racemic mixture of1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (120 mg, 0.18 mmol) was resolved into twoenantiomers on a CHIRALPAK AD chiral HPLC column (25 cm×2 cm) using 15%methanol in pentane to give the title compound:

R_(t) =10 minutes for (-)-1-[2-[3-(3,4-Dichloro-andphenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide.

The (+)- isomer,(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide was also obtained, R_(t) =13 minutes for(+)-1-[2-[3-(3,4-Dichloro-andphenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide. (Retention times determined using an analytical CHIRALPAK ADchiral HPLC column (25 cm×0.46 cm) with 15% methanol in pentane and aflow rate of 1.0 mL/minute.

EXAMPLE 22 Synthesis of1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

22.1 Synthesis of 3-cyano-3-phenyl-pentanedioic acid diethyl ester

Combined phenylacetonitrile (5.85 g, 50.0 mmol) and THF (30 mL). Cooledin a dry-ice/acetone bath. Added dropwise, sodiumbis-(trimethylsilyl)amide (100 mL, 1.0M in THF, 100 mmol, 2 eq.). Afterthe addition was complete, allowed to warm to ambient temperature.Cooled in a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (11mL, 99 mmol). After the addition was complete, warmed to ambienttemperature and stir for 3 h. Partitioned the reaction mixture betweendiethyl ether (200 mL) and water (200 mL). The organic layer wasextracted with H₂ O (3×150 mL), 1N HCl (2×100 mL), 5% NaHCO₃ (2×100 mL),and brine (1×150 mL). Dried over MgSO₄, filtered, and concentrated invacuo to obtain a residue. Chromatographed on silica gel eluting with20% ethyl acetate in hexane to obtain the title compound:

R_(f) =0.23 (silica gel, 20% ethyl acetate in hexane).

22.2 Synthesis of [3-phenyl-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester

Prepared by the method of example 1.2.2 using3-cyano-3-phenyl-pentanedioic acid diethyl ester (37 mmol) and Raneynickel (70 g) to give the title compound:

R_(f) =0.60 (silica gel, 6% methanol in dichloromethane).

22.3 Synthesis of 2-(3-phenyl-5-yl-pyrrolidin-3-yl)-ethanol

Combined (3-phenyl-5-oxo-pyrrolidin-3-yl)-acetic acid ethyl ester (8.71g, 35 mmol) and LiAlH₄ (141 mL, 1M solution in THF, 141 mmol) in THF (20mL). Heated to reflux for 19 h. Cooled in an ice bath. Added H₂ O (5mL), NaOH (5 mL, 15%), and H₂ O (15 mL). The slurry was filtered and thefiltrate was concentrated to obtain a residue. Dissolved the residue indichloromethane and dried it over MgSO₄, filtered, and concentrated thefiltrate in vacuo to obtain a residue which was dried under high vacuumfor 24 h to give the title compound:

R_(f) =0.03 (silica gel, 6% methanol in dichloromethane).

22.4 Synthesis of2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepared by the method of example 3.1 using2-(3-phenyl-pyrrolidin-3-yl)-ethanol (10.47 mmol) and3,4,5-trimethoxy-benzoyl chloride (10.49 mmol). Chromatographed onsilica gel (200 g) eluting with ethyl acetate and then 3% methanol indichloromethane to give the title compound:

R_(f) =0.38 (silica gel, 6% methanol in dichloromethane).

22.5 Synthesis of2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepared by the method of example 3.2 using2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol (2.59mmol) and methanesulfonyl chloride (3.62 mmol) to give the titlecompound:

R_(f) =0.70 (silica gel, 10% methanol in dichloromethane).

22.6 Synthesis of1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepared by the method of example 3.3 using2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(2.59 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (3.3 mmol). Chromatography on silica gel (100 g) elutingsequentially with ethyl acetate, 6% methanol in dichloromethane, and 10%methanol in dichloromethane gave the title compound:

R_(f) =0.41 (silica gel, 10% methanol in dichloromethane).

22A.7 Synthesis of1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

Prepared by the method of example 3.3A using1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (710 mg, 1.24 mmol) and dichloromethane saturated with HCl(gas) (20 mL). The solution was concentrated in vacuo to obtain aresidue. The residue was dried under high vacuum at 56° C. for 18 h toafford the title compound:

Analysis: calculated for C₃₄ H₄₂ ClN₃ O₅.0.91 H₂ O C 65.38; H 7.07; N6.73; Found C 65.00; H 6.97; N 6.49.

EXAMPLE 23 Synthesis of1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

23.1 Synthesis of 3-cyano-3-(3,4-dimethoxy-phenyl)-pentanedioic aciddiethyl ester

Combined 3,4-dimethoxy-phenyl-acetonitrile (20.0 g, 113 mmol) and THF(100 mL). Cooled in a dry-ice/acetone bath. Added dropwise, sodiumbis(trimethylsilyl)amide (226 mL, 1.0M in THF, 226 mmol, 2 eq.). Afterthe addition was complete, allowed to warm to 10 ° C. Cooled in adry-ice/acetone bath. Added dropwise, ethyl bromoacetate (37.7 g, 226mmol). After the addition was complete, the reaction mixture was allowedto warm to ambient temperature and maintained overnight. Filtered thereaction mixture and concentrated in vacuo to obtain a residue. Theresidue was partitioned between diethyl ether (600 mL) and water (200mL). The organic layer was extracted with water (200 mL), saturated NH₄Cl (2×100 mL), dried over MgSO₄, filtered, and concentrated in vacuo toobtain a residue. Chromatographed on silica gel eluting with ethylacetate/hexane (1:2) to obtain the title compound:

R_(f) =0.42 (silica gel, 1:2 ethyl acetate/hexane).

Analysis: calculated for C₁₈ H₂₃ NO₆ C 61.88; H 6.64; N 4.01; Found C61.79; H 6.62; N 3.91.

23.2 Synthesis of[3-(3,4-dimethoxy-phenyl)-5-oxo-pyrrolidin-3-y1]-acetic acid ethyl ester

Combined 3-cyano-3-(3,4-dimethoxy-phenyl)-pentanedioic acid diethylester (16.8 g, 48.0 mmol), methanol (300 mL) and cobalt (II) chloridehexahydrate (22.8 g, 96.0 mmol). Cooled until the internal temperaturereached 10° C. Added portionwise so as to maintain the reactiontemperature below 20° C., sodium borohydride (44.2 g, 1.17 mol). Afteraddition was complete, the reaction mixture was allowed to warm toambient temperature and stirred over the weekend. Concentrated in vacuoto obtain a residue. Partitioned between 1N HCl (800 mL) anddichloromethane (800 mL). The organic layer was extracted with 1N HCl(2×200 mL). The combined aqueous layers were extracted withdichloromethane (3×100 mL). The organic layers were combined, dried overNa₂ SO₄, filtered, and concentrated in vacuo to obtain a residue. Theresidue was chromatographed on silica gel eluting with ethylacetate/methanol (20:1) to obtain the title compound:

R_(f) =0.27 (silica gel, 20:1 ethyl acetate/methanol), mp=116°-118° C.

Analysis: calculated for C₁₆ H₂₁ NO₅ C 62.53; H 6.89; N 4.56; Found C62.52; H 6.85; N 4.50.

23.3 Synthesis of 2-[3-(3,4-dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol

Combined LiAlH₄ (4.80 g, 127 mmol, 4 eq) and anhydrous THF (200 mL).Added portionwise, a slurry of[3-(3,4-dimethoxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester(9.72 g, 31.6 mmol) in THF (100 mL). After the addition was complete,the reaction was heated at reflux overnight. Cooled in an ice/NaCl bath.Cautiously added H₂ O (4.8 mL), NaOH (4.8 mL, 15%), and H₂ O (19.2 mL).Filtered. Concentrated the filtrate to obtain a residue. Dissolved theresidue in dichloromethane and dried over MgSO₄, filtered, andconcentrated the filtrate in vacuo to obtain a residue which was driedat 0.05 Torr overnight to give the title compound. This material wasused without further purification.

23.4 Synthesis of2-[3-(3,4-dimethoxy-phenyl)-1-3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (2.27 g, 9.03 mmol)and dichloromethane (100 mL) were combined. 4-Methylmorpholine (2.28 mL,22.6 mmol, 2.5 eq.) was added. The mixture was cooled in a ice/NaCl bathand a solution of 3,4,5-trimethoxy-benzoyl chloride (2.19 g, 9.48 mmol)in dichloromethane (30 mL) was added dropwise. After the addition wascomplete, the dry-ice/acetone bath was changed to an ice bath and themixture was allowed to warm to ambient temperature and maintainedovernight. The solution was extracted with 1N HCl (3×100 mL), saturatedK₂ CO₃ (3×100 mL). The organic phase was dried over Na₂ SO₄, filtered,and concentrated in vacuo to obtain a residue. The residue was purifiedby chromatography on silica gel eluting with ethyl acetate/methanol(20:1) to obtain a residue. The residue was dissolved in dichloromethane(50 mL), extracted with water (2×50 mL), dried over Na₂ SO₄, filtered,and concentrated in vacuo to obtain a residue. Heated at 110° C./0.3Torr for 16 h to obtain the title compound: R_(f) =0.14 (silica gel,20:1 ethyl acetate/methanol), mp=60°-62° C.

Analysis: calculated for C₂₄ H₃₁ NO₇, C 64.70; H 7.01; N 3.14; Found C64.40; H 7.21; N 2.85.

23.5 Synthesis of2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepared by the method of example 3.2 using2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(249 mg, 0.55 mmol) and methanesulfonyl chloride (0.76 mmol) to give thetitle compound:

R_(f) =0.73 (silica gel, 10% methanol in dichloromethane).

23.6 Synthesis of1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepared by the method of example 3.3 using2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.55 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (175 mg, 0.73 mmol). Chromatography on silica gel (30 g)eluting sequentially with ethyl acetate, 6% methanol in dichloromethane,and 10% methanol in dichloromethane gave the title compound:

R_(f) =0.39 (silica gel, 10% methanol in dichloromethane).

Analysis: calculated for C₃₆ H₄₅ N₃ O₇.1.7 H₂ O C 65.27; H 7.36; N 6.34;Found C 65.26; H 7.02; N 6.32.

EXAMPLE 24 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

24.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethanol

The method of example 3.1 was used with2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and3,5-bis(trifluoromethyl)-benzoyl chloride (1 mmol) to obtain a residue.Chromatography of the residue on silica gel eluting sequentially with 1%methanol in dichloromethane and then 6% methanol in dichloromethane gavethe title compound.

R_(f) =0.53 (silica gel, 10% methanol in dichloromethane).

24.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

The method of example 3.2 was used with2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-benzoyl)-pyrrolidin-3-yl]-ethanol (0.924 mmol) and methanesulfonylchloride (1.01 mmol) to obtain a residue. Drying the residue under highvacuum at ambient temperature 18 h gave the title compound.

R_(f) =0.68 (silica gel, 10% methanol in dichloromethane).

24.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

The method of example 3.3 was used with2-[3-(3,4-dichloro-phenyl)-1-(3,5-bis-(trifluoromethyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.87 mmol) 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(1.04 mmol) to obtain a residue. Chromatography of the residue on silicagel eluting sequentially with 30% ethyl acetate in hexane, 50% ethylacetate in hexane, 1% methanol in dichloromethane, 3% methanol indichloromethane, and then 6% methanol in dichloromethane gave the titlecompound:

R_(f) =0.41 (silica gel, 10% methanol in dichloromethane).

EXAMPLE 25 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

25.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

The method of example 3.1 was used with2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and3,5-dimethoxy-benzoyl chloride (1 mmol) to prepare the title compound.Chromatography on silica gel eluting sequentially with ethyl acetate andthen 6% methanol in dichloromethane gave the title compound.

R_(f) =0.72 (silica gel, 10% methanol in dichloromethane).

25.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

The method of example 3.2 was used with2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(0.96 mmol) and methanesulfonyl chloride (1.06 mmol) to obtain aresidue. Drying the residue under high vacuum at ambient temperature 18h gave the title compound.

25.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

The method of example 3.3 was used with2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.96 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (1.06 mmol) to prepare the title compound. Chromatographyon silica gel eluting sequentially with ethyl acetate, 6% methanol indichloromethane, and then 10% methanol in dichloromethane gave the titlecompound:

R_(f) =0.55 (silica gel, 10% methanol in dichloromethane).

EXAMPLE 26 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-dimethylamino-ethyl)-amide

26.1 Synthesis of 4-phenyl-piperidine-4-carboxylic acid methyl-esterhydrochloride

4-Phenyl-piperidine-4-carboxylic acid hydrochloride (from example 20.6)(2.67 g, 11 mmol) and methanol (35 mL) were combined. SOCl₂ (0.9 mL,12.34 mmol, 1.1 eq.) was added dropwise. The reaction was heated atreflux for 18 h. The reaction was concentrated in vacuo to obtain aresidue. The residue was slurried in diethyl ether, filtered, and thesolids were rinsed with diethyl ether to give the title compound.

26.2 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-ester

The method of example 3.3 was used with2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid methyl-esterhydrochloride (6 mmol, 1.2 eq.) to obtain a residue. The residue waschromatographed on silica gel eluting sequentially with 1% methanol indichloromethane and then 2% methanol in dichloromethane to give thetitle compound:

R_(f) =0.57 (silica gel, 6% methanol in dichloromethane).

26.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid

1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-ester (0.393 g, 0.60 mmol) and NaOH (6 mL, 1N, 6 mmol) werecombined in ethanol (12 mL). The mixture was stirred for 48 h at ambienttemperature. 1N HCl was added to adjust the pH to 1. The aqueous phasewas extracted with ethyl acetate. The organic phase was dried overMgSO₄, filtered, and concentrated in vacuo to obtain a residue. Theresidue was chromatographed on silica gel eluting sequentially with 10%methanol in dichloromethane and then 20% methanol in dichloromethane.The fractions which contained the title compound were washed with H₂ O,dried over MgSO₄, filtered, and concentrated in vacuo to give the titlecompound:

R_(f) =0.59 (silica gel, 85:10:5 CHCl₃ :CH₃ OH:CH₃ CO₂ H).

26FH.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 2-dimethylamino-ethyl)-amide bis-trifluoroacetate

1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (0.2566 g, 0.4 mmol), N,N-dimethylethylene-diamine (0.05 mL, 0.48mmol), HOBt (65 mg, 0.48 mmol), EDC (92 mg, 0.48 mmol), DIEA (0.08 mL,0.48 mmol) were combined in dichloromethane (20 mL). The mixture wasstirred for 72 h at ambient temperature. The mixture was extracted withH₂ O. The organic phase was dried over MgSO₄, filtered, and concentratedin vacuo to obtain a residue. The residue was chromatographed using aVydac (25×250 mm) C-18 HPLC column to give the title compound:

R_(t) =28 minutes (gradient elution with CH₃ CN/H₂ O(0.1% TFA; flowrate=1.0 ml/min.) 10% CH₃ CN for 10 minutes, 30% CH₃ CN for 15 minutes,40% CH₃ CN for 15 minutes, 50% CH₃ CN for 10 minutes, and then 100% CH₃CN).

EXAMPLE 27 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

27.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

The method of example 3.1 was used with2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and3-methoxy-benzoyl chloride (2 mmol) to obtain a residue. The residue waschromatographed on silica gel eluting sequentially with ethyl acetateand then 6% methanol in dichloromethane to give the title compound.

R_(f) =0.53 (silica gel, 10% methanol in dichloromethane).

27.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

The method of example 3.2 was used with2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol) to obtain a residue.Drying the residue under high vacuum at ambient temperature for 18 hgave the title compound:

R_(f) =0.69 (silica gel, 10% methanol in dichloromethane).

27.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

The method of example 3.3 was used with2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol) to prepare the title compound. Chromatography on silica geleluting sequentially with ethyl acetate, 6% methanol in dichloromethane,and then 10% methanol in dichloromethane gave the title compound:

R_(f) =0.41 (silica gel, 10% methanol in dichloromethane).

27.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

2-[3-(3,4-Dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.54 g), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (173mg, 0.72 mmol) and potassium carbonate (0.25 g, 1.8 mmol) were combinedin THF/H₂ O (20 mL/10 mL) and heated at reflux for 48 hours. Thereaction mixture was diluted with ethyl acetate and extracted withwater. The organic layer was separated, dried over MgSO₄, and evaporatedin vacuo to give a residue. The residue was chromatographed on silicagel eluting sequentially with 1% methanol in dichloromethane, 2%methanol in dichloromethane, 3% methanol in dichloromethane, 6% methanolin dichloromethane, and 10% methanol in dichloromethane to give thetitle compound:

R_(f) =0.48 (silica gel, 10% methanol in dichloromethane).

Exact mass (FAB+): calculated for C₃₂ H₃₆ Cl₂ N₃ O₃ calculated 580.2133.Found 580.2131.

EXAMPLE 28 Synthesis of1-[2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

28.1 Synthesis of 3-cyano-3-(benzo[1,3]dioxol-5-yl)-pentanedioic aciddiethyl ester

Combined 3-(benzo[1,3]dioxol-5-yl)-phenylacetonitrile (25.7 g, 0.159mol) and THF (200 mL). Cooled in a dry-ice/acetone bath. Added dropwise,sodium bis-(trimethylsilyl)amide (318 mL, 1.0M in THF, 0.318 mol, 2eq.). After the addition was complete, allowed to warm to 10° C. Cooledin a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (35.3 mL,0.318 mol). After the addition was complete, warmed to ambienttemperature. Removed the THF by evaporation at reduced pressure.Partitioned the reaction mixture between diethyl ether (200 mL) andwater (200 mL). Extracted the organic layer with saturated NH₄ Clsolution (2×200 mL). Dried over MgSO₄, filtered, and concentrated invacuo to obtain a residue. Chromatographed on silica gel eluting with25% ethyl acetate in hexane to obtain the title compound:

R_(f) =0.32 (silica gel, 25% ethyl acetate in hexane).

Analysis: calculated for C₁₇ H₁₉ NO₆ C 61.25; H 5.75; N 4.20; Found C61.51; H 5.88; N 4.18.

28.2 .Synthesis of[3-(benzo[1,3]dioxol-5-yl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester

Prepare by the method of example 1.2.2 using3-cyano-3-(benzo[1,3]dioxol-5-yl)-pentanedioic acid diethyl ester (89mmol). Chromatograph on silica gel to give the title compound.

28.3 Synthesis of 2-(3-benzo[1,3]dioxol-5-yl-pyrrolidin-3-yl)-ethanol

Prepare by the method of example 1.3.2 using[3-(benzo[1,3]dioxol-5-yl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester (73 mmol). Chromatograph on silica gel to give the title compound.

28.4 Synthesis of2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-(3-benzo[1,3]dioxol-5-yl-pyrrolidin-3-yl)-ethanol (22 mmol) and3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gelto give the title compound.

28.5 Synthesis of2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound. R_(f) =0.60 (silica gel, 6% methanol/dichloromethane).

28.6 Synthesis of1-[2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

28.6.1 Synthesis of1-[2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.22 g, 0.43 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (0.21 g,0.86 mmol). Chromatograph on silica gel elutingsequentially with 50% ethyl acetate/hexane and then 6%methanol/dichloromethane to give the title compound: R_(f) =0.38 (silicagel, 10% methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₅ H₄₂ N₃ O₇ calculated 616.3023.Found 616.3027.

EXAMPLE 29 Synthesis of1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

29.1 Synthesis of2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (405 mg, 1.61.mmol) and dichloromethane (20 mL) were combined. 4-Methylmorpholine (350L, 3.22 mmol, 2 eq.) was added. The mixture was cooled in adry-ice/acetone bath and a solution of 3,4,5-triethoxy-benzoyl chloride(461 mg, 1.69 mmol) in dichloromethane (10 mL) was added dropwise. Afterthe addition was complete, the dry-ice/acetone bath was changed to anice bath and the mixture was stirred for 1 h. Allowed to warm to ambienttemperature and maintained overnight. The solution was extracted with 1NHCl (2×50 mL), saturated NaHCO₃ (50 mL), and H₂ O (50 mL). The organicphase was dried over Na₂ SO₄, filtered, and concentrated in vacuo toobtain a residue. The residue was purified by chromatography on silicagel eluting with ethyl acetate/methanol (20:1) to obtain a residue. Theresidue was dissolved in dichloromethane (50 mL), extracted with water(2×50 mL), dried over Na₂ SO₄, filtered, and concentrated in vacuo toobtain a residue. Heated at 70° C./0.5 Torr for 16 h to obtain the titlecompound: R_(f) =0.31 (silica gel, 20:1 ethyl acetate/methanol),mp=139°-141° C.

29.2 Synthesis of2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-methoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

29.3 Synthesis of1-[2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)--pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 30 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(naphth-2-yl)-piperidine-4-carboxylicacid amide

30.1 Synthesis of2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine.

Combine bis-(2-chloroethyl)amine hydrochloride (500 mmol) anddichloromethane (350 mL). Add dropwise, N,N-diisopropylethylamine (1.1mol). Cool the mixture to -30° C. Add dropwise, a solution ofdi-tert-butyl dicarbonate (550 mmol) in dichloromethane (100 mL). Stirthe mixture and allow it to warm to ambient temperature. Concentrate themixture in vacuo to give a residue. Purify the residue to give the titlecompound.

30.2 Synthesis of1-tert-butoxycarbonyl-4-cyano-4-(naphth-2-yl)-piperidine

Combine naphth-2-ylacetonitrile (10 mmol) and2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol) inDMSO (30 mL). Add portionwise, NaNH₂ (22 mmol). After the addition, stirfor an additional 0.5 h. Pour the contents of the flask over ice (150g). Extract the mixture with dichloromethane. Dry the organic phase overMgSO₄, filter, and concentrate in vacuo to give a residue. Purify togive the title compound.

30.3 Synthesis of 4-cyano-4-(naphth-2-yl)-piperidine

hydrochloride

Combine 1-tert-butoxycarbonyl-4-cyano-4-(naphth-2-yl)-piperidine (3.12mmol) and HCl in dioxane (10 mL, 40 mmol, 4N, 13 eq.) at ambienttemperature for 1 h. Concentrate the solvent in vacuo and dry under highvacuum to give the title compound.

30.4 Synthesis of 4-(naphth-2-yl)-piperidine-4-carboxylic acidhydrochloride

Prepare by the method of example 20.6 using4-cyano-4-(naphth-2-yl)-piperidine hydrochloride (10 mmol) and KOH (0.4mol, 3N). Purify to give the title compound.

30.5 Synthesis of1-tert-butoxycarbonyl-4-(naphth-2-yl)-piperidine-4-carboxylic acid

Prepare by the method of example 20.7 using4-(naphth-2-yl)-piperidine-4-carboxylic acid hydrochloride (10 mmol) anddi-tert-butyl dicarbonate (11 mmol). Purify to give the title compound.

30.6 Synthesis of1-tert-butoxycarbonyl-4-(naphth-2-yl)-piperidine-4-carboxylic acid amide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-(naphth-2-yl)-piperidine-4-carboxylic acid (4mmol) and NH₃ (gas). Purify to give the title compound.

30.7 Synthesis of 4-(naphth-2-yl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 20.10 using1-tert-butoxycarbonyl-4-(naphth-2-yl)-piperidine-4-carboxylic acid amide(3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.

30.8 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(naphth-2-yl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-(naphth-2-yl)-piperidine-4-carboxylic acid amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 31 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-4-yl)-piperidine-4-carboxylicacid amide

31.1 Synthesis of 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-4-piperidine

Prepare by the method of example 30.2 using 4-pyridylacetonitrile (10mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine(11 mmol). Purify to give the title compound.

31.2 Synthesis of 4-cyano-4-(pyridin-4-yl)-piperidine hydrochloride

Prepare by the method of example 30.3 using1-tert-butoxycarbonyl-4-cyano-4-(pyridin-4-yl)-piperidine (3 mmol) andHCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dryunder high vacuum to give the title compound.

31.3 Synthesis of 4-(pyridin-4-yl)-piperidine-4-carboxylic acidhydrochloride

Prepare by the method of example 20.6 using4-cyano-4-(pyridin-4-yl)-piperidine hydrochloride (10 mmol) and KOH (0.4mol, 3N). Purify to give the title compound.

31.4 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-4yl)-piperidine-4-carboxylic acid

Prepare by the method of example 20.7 using4-(pyridin-4-yl)-piperidine-4-carboxylic acid hydrochloride (10 mm anddi-tert-butyl dicarbonate (11 mmol). Purify to give the title compound.

31.5 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acidamide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acid (4.0mmol) and NH₃ (gas). Purify to give the title compound.

31.6 Synthesis of 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 20.10 using1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acidamide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the titlecompound.

31.7 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-4-yl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 32 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylicacid amide

32.1 Synthesis of1-tert-Butoxycarbonyl-4-cyano-4-(pyridin-3-yl)-piperidine

Prepare by the method of example 30.2 using 3-pyridylacetonitrile (10mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine(11 mmol). Purify to give the title compound.

32.2 Synthesis of 4-cyano-4-(pyridin-3-yl)-piperidine hydrochloride

Prepare by the method of example 30.3 using1-tert-butoxycarbonyl-4-cyano-4-(pyridin-3-yl)-piperidine (3 mmol) andHCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dryunder high vacuum to give the title compound.

32.3 Synthesis of 4-(pyridin-3-yl)-piperidine-4-carboxylic acidhydrochloride

Prepare by the method of example 20.6 using4-cyano-4-(pyridin-3-yl)-piperidine hydrochloride (10 mmol) and KOH (0.4mol, 3N). Purify to give the title compound.

32.4 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acid

Prepare by the method of example 20.7 using4-(pyridin-3-yl)-piperidine-4-carboxylic acid hydrochloride (10 mm anddi-tert-butyl dicarbonate (11 mmol). Purify to give the title compound.

32.5 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acidamide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acid (4.0mmol) and NH₃ (gas). Purify to give the title compound.

32.6 Synthesis of 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 20.10 using1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acidamide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the titlecompound.

32.7 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 33 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-2-yl)-piperidine-4-carboxylicacid amide

33.1 Synthesis of1-tert-butoxycarbonyl-4-cyano-4-(pyridin-2-yl)-piperidine

Prepare by the method of example 30.2 using 2-pyridylacetonitrile (10mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine(11 mmol). Purify to give the title compound.

33.2 Synthesis of 4-cyano-4-(pyridin-2-yl)-piperidine hydrochloride

Prepare by the method of example 30.3 using1-tert-butoxycarbonyl-4-cyano-4-(pyridin-2-yl)-piperidine (3 mmol) andHCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dryunder high vacuum to give the title compound.

33.3 Synthesis of 4-(pyridin-2-yl)-piperidine-4-carboxylic acidhydrochloride

Prepare by the method of example 20.6 using4-cyano-4-(pyridin-2-yl)-piperidine hydrochloride (10 mmol) and KOH (0.4mol, 3N). Purify to give the title compound.

33.4 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acid

Prepare by the method of example 20.7 using4-(pyridin-2-yl)-piperidine-4-carboxylic acid hydrochloride (10 mmol)and di-tert-butyl dicarbonate (11 mmol). Purify to give the titlecompound.

33.5 Synthesis of1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acidamide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acid (4mmol) and NH₃ (gas). Purify to give the title compound.

33.6 Synthesis of 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 20.10 using1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acidamide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the titlecompound.

33.7 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-2-yl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 34 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-benzyl-piperidine-4-carboxylicacid amide

34.1 Synthesis of ethyl-(1-tert-butoxycarbonyl-piperidine)-4-carboxylate

Combine ethyl-piperidine-4-carboxylate (10 mmol) and dichloromethane (50mL). Add dropwise, N,N-diisopropylethylamine (11 mmol). Add dropwise, asolution of di-tert-butyl dicarbonate (11 mmol) in dichloromethane (10mL). Stir the mixture at ambient temperature. Extract the mixture with1N HCl and H₂ O. Dry the organic phase over MgSO₄, filter, andconcentrate in vacuo to give a residue. Purify the residue to give thetitle compound.

34.2 Synthesis ofethyl-(4-benzyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylate

Combine lithium diisopropylamide (11 mmol) and THF (100 mL). Cool in adry-ice/acetone bath. Addethyl-(1-tert-butoxycarbonyl-piperidine)-4-carboxylate (10 mmol). Stirfor 2 h. Add dropwise, benzyl bromide (12 mmol) inhexamethylphosphoramide (3 mmol). Stir and allow the mixture to warmslowly. Dilute with ethyl acetate and extract with H₂ O. Dry the organicphase over MgSO₄, filter, and concentrate in vacuo to give a residue.Purify the residue to give the title compound.

34.3 Synthesis of4-benzyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylic acid

Combine ethyl-(4-benzyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylate(0.60 mmol) and NaOH (6 mL, 1N, 6 mmol) in ethanol (12 mL). Stir themixture at ambient temperature. Add 1N HCl to adjust the pH to 1.Extract the aqueous phase with ethyl acetate. Dry the organic phase overMgSO₄, filter, and concentrate in vacuo to obtain a residue. Purify theresidue to give the title compound.

34.4 Synthesis of4-benzyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylic acid amide

Prepare by the method of example 20.8 using4-benzyl-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (4.0 mmol)and NH₃ (gas). Purify to give the title compound.

34.5 Synthesis of 4-benzyl-piperidine-4-carboxylic acid

amide

Prepare by the method of example 20.10 using4-benzyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylic acid amide (3mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.

34.6 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-benzyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-benzyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 35 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide

35.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

35.1.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid pyrrolidine-amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.22 g, 0.42 mmol) and 4-phenyl-piperidine-4-carboxylic acidpyrrolidine-amide hydrochloride (0.13 mmol, 0.42 mmol). Chromatograph onsilica gel eluting sequentially with 50% ethyl acetate/hexane, 2%methanol/dichloromethane, and then 4% methanol/dichloromethane to givethe title compound:

R_(f) =0.50 (silica gel, 6% methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₈ H₄₆ Cl₂ N₃ O₅ calculated 694.2830.Found 694.2814.

EXAMPLE 36 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide

36.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid morpholine-amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

36.1.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.22 g, 0.42 mmol and 4-phenyl-piperidine-4-carboxylic acidmorpholine-amide hydrochloride (0.13 mmol, 0.42 mmol). Chromatograph onsilica gel eluting sequentially with 50% ethyl acetate/hexane, 3%methanol/dichloromethane, and then 6% methanol/dichloromethane to givethe title compound.

Exact mass (FAB+): calculated for C₃₈ H₄₆ Cl₂ N₃ O₆ calculated 710.2764.Found 710.2762.

EXAMPLE 36A Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide hydrochloride

36A.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide hydrochloride

Prepare by the method of example 66.4 using1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide (2.34 g, 3.3 mmol) and dichloromethane saturatedwith hydrochloric acid (100 mL) to give the title compound: R_(f) =0.58(silica gel, 10% methanol/dichloromethane).

EXAMPLE 37 Synthesis of1-[2-[3-(3,4-dichloro-phenyl-1-(3,4,5-trimethoxy-benzoyl)pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide

37.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid piperidine-amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

37.1.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid piperidine-amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.21 g, 0.4 mmol) and 4-phenyl-piperidine-4-carboxylic acidpiperidine-amide hydrochloride (0.12 mmol, 0.4 mmol). Chromatograph onsilica gel eluting sequentially with 50% ethyl acetate/hexane, 2%methanol/dichloromethane, and then 4% methanol/dichloromethane to givethe title compound:

R_(f) =0.41 (silica gel, 5% methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₉ H₄₈ Cl₂ N₃ O₅ calculated 708.2937.Found 708.2971.

EXAMPLE 38 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-amide

38.1 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid methyl-amide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (4.0 mmol)and CH₃ NH₂. Purify to give the title compound.

38.2 Synthesis of 4-phenyl-piperidine-4-carboxylic acid methyl-amide

Prepare by the method of example 20.10 using4-phenyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylic acidmethyl-amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the titlecompound.

38.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid methyl-amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid methyl-amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 39 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide

39.1 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (4.0 mmol)and (CH₃)₂ NH. Purify to give the title compound.

39.2 Synthesis of 4-phenyl-piperidine-4-carboxylic acid dimethyl-amide

Prepare by the method of example 20.10 using4-phenyl-1-tert-butoxycarbonyl-piperidine)-4-carboxylic aciddimethyl-amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give thetitle compound.

39.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoly)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid dimethyl-amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid dimethyl-amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 40 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

40.1 Synthesis of2-[3-[3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and4-chlorobenzoyl chloride (2 mmol). Chromatograph on silica gel to givethe title compound.

40.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature 18 h to obtain the titlecompound.

40.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 41 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

41.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and4-tert-butyl-benzoyl chloride (2 mmol). Chromatograph on silica gel togive the title compound.

41.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature 18 h to obtain the titlecompound.

41.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 42 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

42.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and4-tert-butyl-phenacyl chloride (2 mmol). Chromatograph on silica gel togive the title compound.

42.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature for 18 h to obtain the titlecompound.

42.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

PREPARATION 1 Synthesis of 3-Isopropoxy-phenyl-acetyl chloride

Combine 3-hydroxy-phenyl acetic acid (9.26 g, 60.9 mmol), isopropyliodide (42.6 g, 250 mmol), and acetone (80 mL). Add portionwise,potassium carbonate (16.9 g, 122 mmol). Heat to reflux with vigorousmechanical stirring. After 20 hours, cool to ambient temperature andevaporate in vacuo to give a residue. Partition the residue betweendiethyl ether and 5% sodium hydroxide solution. Extract the organiclayer with water and a saturated sodium chloride solution. Dry theorganic layer over MgSO₄, filter and evaporate in vacuo to obtain aliquid. Bulb-to-bulb distillation gives 3-isopropoxy-phenyl-acetic acidisopropyl ester: bp; 125° C. at 0.2 mm of Hg.

Combine 3-isopropoxy-phenyl-acetic acid isopropyl ester 10.2 g, 43.2mmol) and sodium hydroxide (2.08 g, 51.8 mmol) in 1/1 ethanol/water (80mL). Heat to reflux. After 18 hours, remove the ethanol by evaporationin vacuo and acidify to pH=1 using an aqueous solution with 1Mhydrochloric acid solution. Extract the aqueous solution 3 times withethyl acetate. Extract the combined organic layers with water andsaturated sodium chloride solution. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to obtain 3-isopropoxy-phenyl-aceticacid.

Combine 3-isopropoxy-phenyl-acetic acid (0.5 g, 2.6 mmol) anddichloromethane (5 mL). Cool to -5° C. using a ice-salt bath. Add 2drops of dimethylformamide followed by dropwise addition of oxalylchloride (0.34 g, 2.7 mmol). after 1 hour, warm the reaction mixture toambient temperature. After 2 hours, evaporate the reaction mixture invacuo to give the title compound as a liquid.

EXAMPLE 43 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

43.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and3-isopropoxy-phenacyl chloride (2 mmol). Chromatograph on silica gel togive the title compound. R_(f) =0.44 (silica gel, 5%methanol/dichloromethane).

43.2 Synthesis2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature 18 h to obtain the titlecompound. R_(f) =0.65 (silica gel, 10% methanol/dichloromethane).

43.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

43.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.24 g, 0.5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (0.24 g, 0.98 mmol). Chromatograph on silica gel to givethe title compound: R_(f) =0.45 (silica gel, 6%methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₅ H₄₂ Cl₂ N₃ O₃ calculated 622.2603.Found 622.2597.

PREPARATION 2 Synthesis of 3,4,5-Trimethoxy-phenyl-acetyl chloride

Combine 3,4,5-trimethoxy-phenyl-acetic acid (2.26 g, 10 mmol) anddichloromethane (50 mL). Cool to -5° C. using a ice-salt bath. Add 2drops of dimethylformamide followed by dropwise addition of oxalylchloride (1.74 mL, 20 mmol). after 1 hour, warm the reaction mixture toambient temperature. After 2 hours, evaporate the reaction mixture invacuo to give the title compound as a liquid.

EXAMPLE 44 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

44.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and3,4,5-trimethoxy-phenacyl chloride (2 mmol). Chromatograph on silica gelto give the title compound. R_(f) =0.45 (6% methanol/dichloromethane).

44.22-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature 18 h to obtain the titlecompound. R_(f) =0.57 (6% methanol/dichloromethane).

44.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

44.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.22 g, 0.4 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (0.20 g, 0.8 mmol). Chromatograph on silica gel to givethe title compound.

Exact mass (FAB+): calculated for C₃₅ H₄₂ Cl₂ N₃ O₅ calculated 654.2501.Found 654.2495.

EXAMPLE 45 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

45.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethano

Prepare by the method of example 3.1 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and2-pyridinecarbonyl chloride (2 mmol). Chromatograph on silica gel togive the title compound.

45.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethanol(0.6 mmol) and methanesulfonyl chloride (0.66 mmol). Dry the residueunder high vacuum at ambient temperature 18 h to obtain the titlecompound.

45.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.72 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 46 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

46.1 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 47 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one

47.1 Synthesis of1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile

Combine 1-benzyl-4-oxo-piperidine (100 mmol), 4-fluorophenylamine (110mmol), and toluene (300 mL). Heat at reflux for 3 h with azeotropicremoval of water. Cool to 50° C. Add acetone cyanohydrin (277 mmol).Slowly distill away the acetone. Concentrate the solvent in vacuo toobtain a residue. Chromatograph on silica gel to obtain the titlecompound.

47.2 Synthesis of1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide

Cautiously combine1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile (60 mmol)and concentrated sulfuric acid (270 mL). Let stand for 24 h at ambienttemperature. Cautiously pour the reaction mixture into excess diluteammonium hydroxide solution/ice. Extract with dichloromethane (3×300mL). Combine the dichloromethane extracts and extract them usingsaturated NaHCO₃ solution (3×300 mL). Dry the dichloromethane solutionover magnesium sulfate, filter, and concentrate in vacuo to obtain aresidue. Purify to obtain the title compound.

47.3 Synthesis of8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one

Mix 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide(20 mmol) and hot toluene (240 mL). Adddimethoxy-N,N-dimethylmethanamine (20 mL) and heat at reflux for 48 h.Concentrate in vacuo to obtain a residue. Purify to obtain the titlecompound.

47.4 Synthesis of1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one hydrochloride

Combine8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one (10mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add indropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm toambient temperature and maintain for 1 h. Extract using saturated NaHCO₃(120 mL). Extract the aqueous phase using dichloromethane (120 mL).Combine the organic layers, extract with saturated NaCl, dry over Na₂SO₄, filter, and concentrate in vacuo to obtain a residue. Add anhydrousmethanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo toobtain a residue and purify to obtain the title compound.

47.5 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-onehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 48 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

48.1 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

Mix 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one(20 mmol) and methanol (200 mL). Add to a catalytic amount of PtO₂ andhydrogenate at 50 psi. Remove the PtO₂ by filtration and concentrate invacuo to obtain a residue. Purify to obtain the title compound.

48.2 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (7.5mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.

EXAMPLE 49 Synthesis of3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

49.1 Synthesis of8-tert-butoxycarbonyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane

Combine 1-2-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (15mmol), di-tert-butyl dicarbonate (16 mmol), and chloroform (100 mL).After 24 h, concentrate in vacuo to obtain a residue. Purify to obtainthe title compound.

49.2 Synthesis of8-tert-butoxycarbonyl-3-benzyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane

Combine8-tert-butoxycarbonyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane(12 mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) inseveral portions. After the addition is complete, add benzyl bromide (18mmol). Allow the reaction mixture to warm to ambient temperature. After3 h, cool the reaction vessel using an ice bath and cautiously add 10%aqueous citric acid (20 mL). When gas evolution has ceased, pour into anadditional 20 mL of 10% aqueous citric acid and extract using ethylacetate (3×60 mL). Extract the combined organics with saturated aqueousNaCl, dry over Na₂ SO₄, filter, and concentrate in vacuo to obtain aresidue. Purify to obtain the title compound.

49.3 Synthesis of3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5)decan-4-one

Cool trifluoroacetic acid (20 mL) using an ice bath and add8-tert-butoxycarbonyl-3-benzyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane(10 mmol). After 1 h, dilute with diethyl ether (150 mL), filter toobtain a residue. Purify to obtain the title compound.

49.4 Synthesis of3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-onetrifluoroacetate (7.5 mmol, 1.5 eq.). Chromatograph on silica gel togive the title compound.

EXAMPLE 50 Synthesis of3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

50.1 Synthesis of8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Combine 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile (32mmol) and dichloromethane (100 mL). Add chlorosulfonyl isocyanate (20mmol) in dropwise fashion with water bath cooling so as to maintain thetemperature of the reaction mixture between 20° and 30° C. After 30minutes, concentrate the reaction mixture in vacuo to obtain a residue.Add 1N HCl (100 mL) and heat at reflux for 1 h. Cool in an ice bath andadjust the pH to 5.5 using 5N NaOH. Filter to obtain a residue. Washwith diethyl ether and dry in vacuo. Purify to obtain the titlecompound.

50.2 Synthesis of3,8-dibenzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Combine8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (12mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) in severalportions. After the addition is complete, add benzyl bromide (18 mmol).Allow the reaction mixture to warm to ambient temperature. After 3 h,cool the reaction vessel using an ice bath and cautiously add 10%aqueous citric acid (20 mL). When gas evolution has ceased, pour into anadditional 20 mL of 10% aqueous citric acid and extract using ethylacetate (3×60 mL). Extract the combined organics with saturated aqueousNaCl, dry over Na₂ SO₄, filter, and concentrate in vacuo to obtain aresidue. Purify to obtain the title compound.

50.3 Synthesis of3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Combine3,8-dibenzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione(10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add indropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm toambient temperature and maintain for 1 h. Extract using saturated NaHCO₃(120 mL). Extract the aqueous phase using dichloromethane (120 mL).Combine the organic layers, extract with saturated NaCl, dry over Na₂SO₄, filter, and concentrate in vacuo to obtain a residue. Add anhydrousmethanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo toobtain a residue and purify to obtain the title compound.

50.4 Synthesis of3-benzyl-8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dionehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 51 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

51.1 Synthesis of1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Combine8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (10mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add indropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm toambient temperature and maintain for 1 h. Extract using saturated NaHCO₃(120 mL). Extract the aqueous phase using dichloromethane (120 mL).Combine the organic layers, extract with saturated NaCl, dry over Na₂SO₄, filter, and concentrate in vacuo to obtain a residue. Add anhydrousmethanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo toobtain a residue and purify to obtain the title compound.

51.2 Synthesis of8-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione

Combine the2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5.0 mmol), 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dionehydrochloride (7.5 mmol, 1.5 eq.), N,N-diisopropylethylamine (15 mmol),and DMF (8 mL). Heat the mixture at 85° C. for 48 h. Cool to ambienttemperature and add ethyl acetate (100 mL). Extract with water (25 mL),1N HCl (2×25 mL), saturated NaHCO₃ (25 mL), and saturated NaCl (25 mL).Dry over MgSO₄, filter, and concentrate in vacuo to obtain a residue.Purify to obtain the title compound.

EXAMPLE 52 Synthesis of1-[2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

52.1 Synthesis of 3-cyano-3-(3-trifluoromethyl-phenyl)-pentanedioic aciddiethyl ester

Prepare by the method of example 1.1.2 using3-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate(0.325 mol). Chromatograph on silica gel to give the title compound.

52.2 Synthesis of[3-(3-trifluoromethyl-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester

Prepare by the method of example 1.2.2 using3-cyano-3-(3-trifluoromethyl-phenyl)-pentanedioic acid diethyl ester (89mmol). Chromatograph on silica gel to give the title compound.

52.3 Synthesis of2-[3-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 1.3.2 using[3-(3-trifluoromethyl-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester (73 mmol). Chromatograph on silica gel to give the title compound.

52.4 Synthesis of2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gelto give the title compound.

52.5 Synthesis of2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

52.6 Synthesis of1-[2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 53 Synthesis of1-[2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

53.1 Synthesis of 3-cyano-3-(thiophen-2-yl)-pentanedioic acid diethylester

Prepare by the method of example 1.1.2 using thiophen-2-yl-acetonitrile(0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silicagel to give the title compound.

53.2 Synthesis of [3-(thiophen-2-yl)-5-oxo-pyrrolidin-3-yl]-acetic acidethyl ester

Prepare by the method of example 1.2 using3-cyano-3-(thiophen-2-yl)-pentanedioic acid diethyl ester (28 mmol),cobalt (II) chloride hexahydrate (55.5 mmol), and NaBH₄ (290 mmol).Chromatograph on silica gel to give the title compound.

53.3 Synthesis of 2-[3-(thiophen-2-yl)-pyrrolidin-3-yl)-ethanol

Prepare by the method of example 1.3.2 using[3-(thiophen-2-yl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (73mmol). Chromatograph on silica gel to give the title compound.

53.4 Synthesis of2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(thiophen-2-yl)-pyrrolidin-3-yl]-ethanol (23 mmol) and3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gelto give the title compound.

53.5 Synthesis of2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

53.6 Synthesis of1-[2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 54 Synthesis of1-[2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

54.1 Synthesis of 3-cyano-3-(pyridin-3-yl)-pentanedioic acid diethylester

Prepare by the method of example 1.1.2 using pyridin-3-yl-acetonitrile(0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silicagel to give the title compound.

54.2 Synthesis of [3-(pyridin-3-yl)-5-oxo-pyrrolidin-3-yl]-acetic acidethyl ester

Prepare by the method of example 1.2.2 using3-cyano-3-(pyridin-3-yl)-pentanedioic acid diethyl ester (89 mmol).Chromatograph on silica gel to give the title compound.

54.3 Synthesis of 2-[3-(pyridin-3-yl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 1.3.2 using[3-(pyridin-3-yl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (73mmol). Chromatograph on silica gel to give the title compound.

54.4 Synthesis of2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(pyridin-3-yl)-pyrrolidin-3-yl]-ethanol (23 mmol) and3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gelto give the title compound.

54.52-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

54.6 Synthesis of1-[2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 55 Synthesis of1-[2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

55.1 Synthesis of 3-cyano-3-(2-fluoro-phenyl)-pentanedioic acid diethylester

Prepare by the method of example 1.1.2 using 2-fluorophenylacetonitrile(0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silicagel to give the title compound.

55.2 Synthesis of [3-(2-fluoro-phenyl)-5-oxo-pyrrolidin-3-yl]-aceticacid ethyl ester

Prepare by the method of example 1.2.2 using3-cyano-3-(2-fluoro-phenyl)-pentanedioic acid diethyl ester (89 mmol).Chromatograph on silica gel to give the title compound.

55.3 Synthesis of 2-[3-(2-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 1.3.2 using[3-(2-fluoro-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (73mmol). Chromatograph on silica gel to give the title compound.

55.4 Synthesis of2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(2-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gelto give the title compound.

55.5 Synthesis of2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

55.6 Synthesis of1-[2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol ) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

EXAMPLE 56 Synthesis of1-[2-[3-(4-hydroxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

56.1 Synthesis of 4-(tert-butyldimethylsilyloxy)-phenylacetonitrile

Combine tert-butyldimethylsilyl chloride (0.460 mol), imidazole (0.600mol) and DMF (125 mL). Add 4-hydroxyphenylacetonitrile (0.400 mol) andmaintain at ambient temperature for 16 h. Dilute with ether (500 mL),extract with water (4×75 mL), saturated sodium chloride (75 mL), dryover MgSO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph on silica gel to obtain the title compound.

56.2 Synthesis of3-cyano-3-[4-(tert-butyldimethyl-silyloxy)-phenyl]-pentanedioic aciddiethyl ester

Prepare by the method of example 1.1.2 using4-(tert-butyldimethylsilyloxy)-phenyl-acetonitrile (0.161 mol) and ethylbromoacetate (0.325 mol). Chromatograph on silica gel to give the titlecompound.

56.3 Synthesis of[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-aceticacid ethyl ester

Prepare by the method of example 1.2.2 using3-cyano-3-[4-(tert-butyldimethylsilyloxy)-phenyl]-pentanedioic aciddiethyl ester (89 mmol). Chromatograph on silica gel to give the titlecompound.

56.4 Synthesis of2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 1.3.2 using[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-aceticacid ethyl ester (73 mmol). Chromatograph on silica gel to give thetitle compound.

56.5 Synthesis of2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-ethanol(23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatographon silica gel to give the title compound.

56.6 Synthesis of2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl]-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of example 3.2 using2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(8 mmol) and methanesulfonyl chloride (11 mmol) to give the titlecompound.

56.7 Synthesis of1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(12 mmol). Chromatograph on silica gel to give the title compound.

56.8 Synthesis of1-[2-[3-(4-hydroxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Combine1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (6 mmol) and THF (20 mL). Cool using an ice bath. Add a 1MTHF solution of tetrabutylammonium fluoride (7 mL) in dropwise fashion.After 30 minutes, concentrate in vacuo to obtain a residue. Adddichloromethane (50 mL) to the residue. Extract with water (3×15 mL),dry over Na₂ SO₄, filter, and concentrate in vacuo to obtain a residue.Purify to obtain the title compound.

EXAMPLE 57 Synthesis of1-[2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

57.1 Synthesis of 3-cyano-3-(4-trifluoromethyl-phenyl)-pentanedioic aciddiethyl ester

Prepare by the method of example 1.1.2 using4-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate(0.325 mol). Chromatograph on silica gel to give the title compound.

57.2 Synthesis of[3-(4-trifluoromethyl-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester

Prepare by the method of example 1.2.2 using3-cyano-3-(4-trifluoromethyl-phenyl)-pentanedioic acid diethyl ester (89mmol). Chromatograph on silica gel to give the title compound.

57.3 Synthesis of2-[3-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 1.3.2 using[3-(4-trifluoromethyl-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethylester (73 mmol). Chromatograph on silica gel to give the title compound.

57.4 Synthesis of 3-isopropoxybenzoic acid

Combine 3-hydroxybenzoic acid (100 mmol), 2-iodopropane (500 mmol), K₂CO₃ (300 mmol), and 2-butanone (300 mL). Heat at reflux for 72 h.Concentrate in vacuo to obtain a residue. Add water (500 mL) and cool inan ice bath. Adjust to pH 1 by dropwise addition of concentrated HCl.Extract with dichloromethane (3×200 mL). Extract the combined organiclayers with water (200 mL), dry over Na₂ SO₄, filter, and concentrate invacuo to obtain a residue. Purify to obtain the title compound.

57.5 Synthesis of 3-isopropoxy-benzoyl chloride

Combine 3-isopropoxybenzoic acid (50 mmol) and dichloromethane (100 mL).Cool in an ice bath. Add in dropwise fashion, oxalyl chloride (55 mmol).Allow the reaction mixture to warm to ambient temperature. After 2 h,concentrate in vacuo to obtain a residue. Use the title compound withoutfurther purification.

57.6 Synthesis of2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Prepare by the method of example 3.1 using2-[3-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and3-isopropoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel togive the title compound.

57.7 Synthesis of2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-bromide

Combine2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(10 mmol), carbon tetrabromide (12.5 mmol), and dichloromethane (15 mL).Cool in an ice bath. Add in portions, triphenylphosphine (15 mmol).After 1 h, concentrate in vacuo to obtain a residue. Purify to obtainthe title compound.

57.8 Synthesis of1-[2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Combine2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-bromide(8 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12mmol), K₂ CO₃ (36 mmol), KI (0.8 mmol), and THF/H₂ O (3/1, 80 mL). Heatat reflux for 72 h. Concentrate in vacuo to remove THF and extract withdichloromethane (2×50 mL). Extract the combined organic layers usingwater (50 mL). Dry over MgSO₄, filter, and concentrate in vacuo toobtain a residue. Chromatograph on silica gel to obtain the titlecompound.

EXAMPLE 58 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(thiophen-2-yl)-piperidine-4-carboxylicacid amide

58.1 Synthesis of1-tert-butoxycarbonyl-4-cyano-4-(thiophen-2-yl)-piperidine

Prepare by the method of example 30.2 using 2-thiopheneacetonitrile (10mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine(11 mmol). Purify to give the title compound.

58.2 Synthesis of 4-cyano-4-(thiophen-2-yl)-piperidine hydrochloride

Prepare by the method of example 30.3 using1-tert-butoxycarbonyl-4-cyano-4-(thiophen-2-yl)-piperidine (3 mmol) andHCl in dioxane (4N, 40 mmol). Concentrate the solvent in vacuo and dryunder high vacuum to give the title compound.

58.3 Synthesis of 4-(thiophen-2-yl)-piperidine-4-carboxylic acidhydrochloride

Prepare by the method of example 20.6 using4-cyano-4-(thiophen-2-yl)-piperidine hydrochloride (10 mmol) and KOH(0.4 mol, 3N). Purify to give the title compound.

58.4 Synthesis of1-tert-butoxycarbonyl-4-(thiophen-2-yl)-piperidine-4-carboxylic acid

Prepare by the method of example 20.7 using4-(thiophen-2-yl)-piperidine-4-carboxylic acid hydrochloride (10 mmol)and di-tert-butyl dicarbonate (11 mmol). Purify to give the titlecompound.

58.5 Synthesis of1-tert-butoxycarbonyl-4-(thiophen-2-yl)-piperidine-4-carboxylic acidamide

Prepare by the method of example 20.8 using1-tert-butoxycarbonyl-4-(thiophen-2-yl)-piperidine-4-carboxylic acid(4.0 mmol) and NH₃ (gas). Purify to give the title compound.

58.6 Synthesis of 4-(thiophen-2-yl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 20.10 using1-tert-butoxycarbonyl-4-(thiophen-2-yl)-piperidine-4-carboxylic acidamide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the titlecompound.

58.7 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(thiophen-2-yl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-(thiophen-2-yl)-piperidine-4-carboxylic acid amidehydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to givethe title compound.

EXAMPLE 59 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

59.1 Synthesis of4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one

Combine4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one(as prepared in example 11.3) (5 mmol) and 3,4,5-trimethoxy-benzoylchloride (5.0 mmol) in N,N-dimethylaniline (20 mL). Heat to 90° C. andstir for 24 h. Concentrate in vacuo. Partition the reaction mixturebetween dichloromethane and H₂ O. Separate the organic layer, dry overMgSO₄, filter, and concentrate in vacuo to obtain a residue. Purify togive the title compound.

59.2 Synthesis of4-(3,4-dichloro-phenyl)-4-(2-hydroxy-ethyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one

Prepare according to the method of example 11.5 using4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title Compound.

59.3 Synthesis of2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare according to the method of example 3.2 using4-(3,4-dichloro-phenyl)-4-2-hydroxy-ethyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one(5 mmol) and methanesulfonyl chloride (6 mmol). Dry under high vacuum atambient temperature for 18 h to give the title compound.

59.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 3.3 using2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 60 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

60.1 Synthesis of4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-pyrrolidine

Prepare according to the method of example 1.3.2 using4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl]-pyrrolidin-2-one(as prepared in example 11.3) (3 mmol), LiAlH₄ (18 mmol) H₂ SO₄(99.999%) (9 mmol). Purify to give the title compound.

60.2 Synthesis of4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine

Combine4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-pyrrolidine(10 mmol), K₂ CO₃ (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10mmol) in THF/H₂ O (4/1, 200 mL). Heat to reflux and stir for 16 h.Concentrate in vacuo to obtain a residue. Dilute the residue with ethylacetate and extract with H₂ O. Separate the layers, dry the organiclayer over MgSO₄, filter, and concentrate in vacuo. Chromatograph onsilica gel to give the title compound.

60.3 Synthesis of4-(3,4-dichloro-phenyl)-4-2-hydroxy-ethyl-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine

Prepare according to the method of example (11.5) using4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title compound.

60.4 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl-bromide

Prepare according to the method of example 57.7 using4-(3,4-dichloro-phenyl)-4-2-hydroxy-ethyl-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine(5 mmol), carbon tetrabromide (6.3 mmol), and triphenylphosphine (7.5mmol). Purify to obtain the title compound.

60.5 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 57.8 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl-bromide(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 61 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

61.1 Synthesis of2-(3,4-dichloro-phenyl)-5-(tetrahydro-pyran-2-yloxy)-pentanenitrile

Prepare according to the method of example 11.1 using3,4-dichlorophenylacetonitrile (50 mmol) and2-(3-bromo-propoxy)-tetrahydro-pyran (50 mmol). Chromatograph on silicagel to give the title compound.

61.2 Synthesis ofethyl-[3-cyano-3-(3,4-dichloro-phenyl)-6-(tetrahydro-pyran-2-yloxy)]-hexanoate

Prepare according to the method of example 11.2 using2-(3,4-dichloro-phenyl)-5-(tetrahydro-pyran-2-yloxy)-pentane nitrile (34mmol) and ethyl bromoacetate (38 mmol, 1.1 eq.). Chromatograph on silicagel to give the title compound.

61.3 Synthesis of4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one

Prepare according to the method of example 11.3 usingethyl-[3-cyano-3-(3,4-dichloro-phenyl)-6-(tetrahydro-pyran-2-yloxy)]-hexanoate(24 mmol) and Raney nickel (30 g). Chromatograph on silica gel to givethe title compound.

61.4 Synthesis of4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine

Prepare according to the method of example 1.3.2 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one(3 mmol), LiAlH₄ (18 mmol) H₂ SO₄ (99.999%) (9 mmol). Purify to give thetitle compound.

61.5 Synthesis of4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine

Prepare by the method of example 3.1 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine(2 mmol) and 3,4,5-trimethoxy-benzoyl chloride (2 mmol). Chromatographon silica gel to give the title compound.

61.6 Synthesis of4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine

Prepare according to the method of example 11.5 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title compound.

61.7 Synthesis of3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl-methanesulfonate

Prepare according to the method of example 3.2 using4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine(5 mmol) and methanesulfonyl chloride (6 mmol). Dry under high vacuum atambient temperature for 18 h to give the title compound.

61.8 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 3.3 using3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 62 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

62.1 Synthesis of4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine

Combine4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine(10 mmol), K₂ CO₃ (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10mmol) in THF/H₂ O (4/1, 200 mL). Heat to reflux and stir for 16 h.Concentrate in vacuo to obtain a residue. Dilute the residue with ethylacetate and extract with H₂ O. Separate the layers, dry the organiclayer over MgSO₄, filter, and concentrate in vacuo. Chromatograph onsilica gel to give the title compound.

62.2 Synthesis of4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine

Prepare according to the method of example 11.5 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title compound.

62.3 Synthesis of3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl-bromide

Prepare according to the method of example 57.7 using4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine (5 mmol), carbon tetrabromide (6.3 mmol),and triphenylphosphine (7.5 mmol). Purify to obtain the title compound.

62.4 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 57.8 using3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl-bromide(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 63 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

63.1 Synthesis of4-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one

Prepare according to the procedure of example 11.4 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one(2.79 mmol) and 3,4,5-trimethoxy-benzyl bromide (5.9 mmol).Chromatograph on silica gel to give the title compound.

63.2 Synthesis of4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-2-one

Prepare according to the method of example 11.5 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-2-one(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title compound.

63.3 Synthesis of3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate

Prepare according to the method of example 3.2 using4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-2-one(5 mmol) and methanesulfonyl chloride (6 mmol). Dry under high vacuum atambient temperature for 18 h to give the title compound.

63.4 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 3.3 using3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 64 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

64.1 Synthesis of4-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one

Prepare according to the procedure of example 59.1 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one(5.0 mmol) and 3,4,5-trimethoxy-benzoyl chloride (5.0 mmol).Chromatograph on silica gel to give the title compound.

64.2 Synthesis of4-(3,4-Dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one

Prepare according to the method of example 11.5 using4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one(3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silicagel to give the title compound.

64.3 Synthesis of3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate

Prepare according to the method of example 3.2 using4-(3,4-dichloro-phenyl)-4-(3-hydroxy-propyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one(5 mmol) and methanesulfonyl chloride (6 mmol). Dry under high vacuum atambient temperature for 18 h to give the title compound.

64.4 Synthesis of1-[3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare according to the method of example 3.3 using3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate(5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the titlecompound.

EXAMPLE 65 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

65.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol

Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (260 mg,1 mmol) and and potassium carbonate (0.69 g, 5 mmol) in ethylacetate/water (10 mL/10 mL). Cool in an ice-bath. Add a solution oftriethoxy-benzoyl chloride (1.2 mmol) in ethyl acetate (10 mL). After 1hour, dilute with ethyl acetate and extract with 1M hydrochloric acidsolution, 5% sodium bicarbonate solution, and water. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give the titlecompound: R_(f) =0.43 (silica gel, 6% methanol/dichloromethane).

65.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of Example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethanol(1 mmol) and methanesulfonyl chloride (0.09 mL, 1.1 mmol) to give thetitle compound: R_(f) =0.61 (silica gel, 6% methanol indichloromethane).

65.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate((1 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.29 g, 1.2 mmol). Chromatograph on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and then 6% methanol/dichloromethane togive the title compound:

R_(f) =0.36 (silica gel, 10% methanol in dichloromethane).

Exact mass (FAB+): calculated for C₃₇ H₄₆ Cl₂ N₃ O₅ calculated 682.2815.Found 682.2799.

EXAMPLE 66 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide hydrochloride

66.1 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide

Prepare by the method of Example 20.9 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.6 g, 5.2mmol) and 4-methylpiperazine (1.2 mL, 10.5 mmol) to give the titlecompound: R_(f) =0.54 (silica gel, 10% methanol/dichloromethane).

66.2 Synthesis of 4-phenyl-piperidine-4-carboxylic acid4-methylpiperazine-amide hydrochloride

Prepare by the method of Example 20.10 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid4-methylpiperazine-amide to give the title compound.

66.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid4-methylpiperazine-amide hydrochloride (2.8 g, 3.9 mmol). Chromatographon silica gel eluting sequentially with 50% ethyl acetate/hexane, 3%methanol/dichloromethane, and then 6% methanol/dichloromethane to givethe title compound.

66.3.2 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide

Prepare by the method of Example 26FH.5 using1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (0.18 g, 0.3 mmol) and 4-phenyl-piperidine-4-carboxylic acid4-methylpiperazine-amide hydrochloride (0.7 mL, 0.6 mmol). Chromatographon silica gel eluting with 6% methanol/dichloromethane to give the titlecompound.

Exact mass (FAB+): calculated for C₃₉ H₄₉ Cl₂ N₄ O₅ calculated 723.3080.Found 723.3067.

66A.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide hydrochloride

Dissolve1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide (1.96 g, 2.71 mmol) in dichloromethane (20mL). This solution was combined with a saturated solution ofhydrochloric acid in dichloromethane (20 mL) and the mixture was stirredfor 1 hour. The reaction mixture was evaporated in vacuo and hexane wasadded. This mixture was evaporated in vacuo and diethyl ether was added.The diethyl ether mixture was evaporated in vacuo to give a solid. Thesolid was dried in vacuo to give the title compound.

Exact mass (FAB+): calculated for C₃₉ H₄₉ Cl₂ N₄ O₅ calculated 723.3080.Found 723.3073.

EXAMPLE 67 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide hydrochloride

67.1 Synthesis of 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide

Prepare by the method of Example 20.9 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (7 mmol) and2-morpholino-ethylamine (7 mmol) to give the title compound: R_(f) =0.49(silica gel, 6% methanol/dichloromethane).

67.2 Synthesis of 4-phenyl-piperidine-4-carboxylic acid(2-morpholino-ethyl)-amide hydrochloride

Prepare by the method of Example 20.10 using1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid(2-morpholino-ethyl)-amide to give the title compound.

67.3.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid(2-morpholino-ethyl)-amide hydrochloride (1.87 g, 35.2 mmol).Chromatograph on silica gel eluting sequentially with 50% ethylacetate/hexane and then 6% methanol/dichloromethane to give the titlecompound.

67.3.2 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (2-morpholino-ethyl)-amide

Prepare by the method of Example 26FH.5 using1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid (0.16 g, 0.625 mmol) and 4-phenyl-piperidine-4-carboxylic acid(2-morpholino-ethyl)-amide hydrochloride (0.07 mL, 0.5 mmol).Chromatograph on silica gel eluting with 6% methanol/dichloromethane togive the title compound: R_(f) =0.34 (silica gel, 10%methanol/dichloromethane).

Exact mass (FAB+): calculated for C₄₀ H₅₁ Cl₂ N₄ O₆ calculated 753.3191.Found 753.3186.

67A.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide hydrochloride

Prepare by the method of example 66A.1 using1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide to give the title compound: R_(f) =0.53(silica gel, 10% methanol/dichloromethane).

EXAMPLE 68 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

68.1 Synthesis of3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine

Prepare by the method of Example 1.4 using2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.26 g, 1 mmol) and4-methoxy-benzoyl chloride (2 mmol) to give the title compound: R_(f)=0.44 (silica gel, 6% methanol in dichloromethane).

68.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of Example 1.5 using3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-3-(2-hydroxy-ethyl)-pyrrolidine(0.24 g, 0.62 mmol) and methanesulfonyl chloride (0.62 mmol) to give thetitle compound: R_(f) =0.57 (silica gel, 6% methanol indichloromethane).

68.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.63 mmol) and 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride (0.3 g). Purify by chromatographed on silica gel elutingsequentially with 50% ethyl acetate/hexane, 4% methanol/dichloromethane,and then 6% methanol/dichloromethane to give the title compound:

R_(f) =0.58 (silica gel, 10% methanol in dichloromethane).

EXAMPLE 69 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

69.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethanol

Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (286 mg,1.1 mmol), 3,4,5-trifluoro-benzoic acid (1 mmol),N,N-diisopropylethylamine (0.19 mL, 1.1 mmol),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (0.21g, 1.1 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.15 g, 1.1mmol) in dichloromethane (10 mL). After 18 hour, dilute withdichloromethane and extract with 1M hydrochloric acid solution, 5%sodium bicarbonate solution, and water. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound: R_(f)=0.45 (silica gel, 10% methanol/dichloromethane).

69.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of Example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethanol(1 mmol) and methanesulfonyl chloride (0.09 mL, 1.1 mmol) to give thetitle compound: R_(f) =0.50 (silica gel, 6% methanol indichloromethane).

69.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trifluoro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(1 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(0.29 g, 1.2 mmol). Chromatograph on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and then 6% methanol/dichloromethane togive the title compound:

R_(f) =0.45 (silica gel, 10% methanol in dichloromethane).

Exact mass (FAB+): calculated for C₃₇ H₄₆ Cl₂ N₃ O₅ calculated 682.2815.Found 682.2799.

EXAMPLE 70 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dibromo-4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

70.1 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethanol

3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (10.4 mg, 40mmol) was combined with di-tert-butyl dicarbonate (8.7 g, 40 mmol) inDMF/ethyl acetate (200 mL/200 mL) and the mixture was allowed to stir atambient temperature for 18 h. Dilute with ethyl acetate and extract with1M hydrochloric acid solution, 5% sodium bicarbonate solution, andwater. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give the title compound: R_(f) =0.57 (silica gel, 10%methanol/dichloromethane).

70.2 Synthesis of2-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethyl-methanesulfonate

Prepare by the method of Example 3.2 using2-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethanol(16.18 g) and methanesulfonyl chloride (3.41 mL, 44 mmol). Chromatographon silica gel eluting with 6% methanol/dichloromethane to give the titlecompound:

R_(f) =0.79 (silica gel, 10% methanol in dichloromethane).

70.3 Synthesis of1-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Combine2-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethyl-methanesulfonate(40 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride(19.26 g, 80 mmol), and potassium carbonate (33.2 g, 240 mmol) inTHF/water (200 mL/200 mL). Heat at reflux for 18 hours. The reactionmixture is diluted with ethyl acetate and extracted with water. Theorganic layer is separated, dried over MgSO₄, and evaporated in vacuo togive a residue. The residue was chromatographed on silica gel elutingsequentially with 50% ethyl acetate/hexane and then 6% methanol indichloromethane to give the title compound:

R_(f) =0.41 (silica gel, 10% methanol in dichloromethane).

70.4 Synthesis of1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride

Combine1-[3-(3,4-dichloro-phenyl)-1-tert-butoxycarbonyl-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (17.78 g, 32.4 mmol) and a saturated solution of hydrochloricacid in dichloromethane (500 mL). After 1 hour, evaporate in vacuo togive the title compound.

70.5 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dibromo-4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Combine1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (241 mg, 0.41 mmol),3,5-dibromo-4-methoxy-benzoic acid (0.23 g, 0.75 mmol),N,N-diisopropylethylamine (0.75 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.75mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.75 g, 1.1 mmol) indichloromethane (10 mL). After 18 hour, dilute with dichloromethane andextract with 1M hydrochloric acid solution, 5% sodium bicarbonatesolution, and water. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with 50% ethyl acetate/hexane and then6% methanol/dichloromethane to give the title compound:

R_(f) =0.35 (silica gel, 10% methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₂ H₃₄ Br₂ Cl₂ N₃ O₃ calculated736.0344. Found 736.0330.

EXAMPLE 71 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-[3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

71.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (240 mg, 0.4 mmol) and3,5-dimethoxy-4-(ethoxy-carboxyloxy)-benzoic acid (0.20 g, 0.75 mmol) togive a residue. Chromatograph the residue on silica gel elutingsequentially with 50% ethyl acetate/hexane and then 6%methanol/dichloromethane to give the title compound: R_(f) =0.35 (silicagel, 10% methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₆ H₄₂ Cl₂ N₃ O₇ calculated 698.2399.Found 698.2402.

EXAMPLE 72 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

72.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (480 mg, 1 mmol) and3,5-di-tert-butyl-4-hydroxy-benzoic acid (0.25 g, 1 mmol) to give aresidue. Chromatograph the residue on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and then 6% methanol/dichloromethane togive the title compound: R_(f) =0.52 (silica gel, 10%methanol/dichloromethane).

Exact mass (FAB+): calculated for C₃₉ H₅₀ Cl₂ N₃ O₃ calculated 678.3229.Found 678.3201.

EXAMPLE 73 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-methyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

73.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-methyl-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (240 mg, 0.5 mmol) and3,5-di-methoxy-4-methyl-benzoic acid (0.22 g, 0.55 mmol) to give aresidue. Chromatograph the residue on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and then 6% methanol/dichloromethane togive the title compound: R_(f) =0.43 (silica gel, 10%methanol/dichloromethane).

PREPARATION 3 Synthesis of 4-phenyl-piperidine-4-carboxylic acid amidehydrochloride

4-Phenyl-4-cyano-piperidine hydrochloride (10 g, 44.9 mmol), Benzylbromide (5.4 mL, 45.4 mmol), and potassium carbonate (25.2 g, 182.3mmol) were combined in THF/water (80 mL/20 mL). After 18 hours thereaction mixture was partitioned between water and dichloromethane. Theorganic layer was separated and extracted with water, dried over MgSO₄,filtered and evaporated in vacuo to give a residue. The residue wasrecrystallized from hexane to give 4-phenyl-4-cyano-1-benzyl-piperidineas a solid: mp=73°-74° C.

Synthesis of 4-phenyl-1-benzyl-piperidine-4-carboxylic acid amideN-oxide

4-Phenyl-4-cyano-1-benzyl-piperidine (535 g, 1940 mmol) was combinedwith aqueous sodium hydroxide (85 mL, 50% by weight) and ethanol (5 L)and the mixture was heated to 50° C. The heating was removed, and asolution of hydrogen peroxide (856 mL, 30% by weight in water) was addedat such a rate that the temperature of the reaction mixture does notrise above 50° C. The reaction mixture was then stirred at 50° C. for 20hours. The reaction mixture was diluted with water (3 L) and the ethanolwas removed in vacuo at 35° C. Cooling the reaction mixture to ambienttemperature gave a solid which was collected by filtration, rinsed withwater, and air dried to give 4-phenyl-1-benzyl-piperidine-4-carboxylicacid amide N-oxide.

Synthesis of 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride

4-Phenyl-1-benbyl-piperidine-4-carboxylic acid amide n-oxide (529 g,1700 mmol) and 10% palladium-on-carbon (25 g) and acetic acid (5 L) werecombined in an autoclave. The autoclave was flushed with nitrogen andthen was charged with 255 psi of hydrogen. Stirring was initiated, andthe autoclave was recharged with hydrogen as required to maintain thepressure above 100 psi. When hydrogen consumption stopped the autoclavewas flushed with nitrogen and the catalyst was removed by filtration.The filtrate was evaporated in vacuo to give a residue. The residue wasdissolved in ethyl acetate (5 L), acidified by the addition of 12Maqueous hydrochloric acid solution (150 mL), and heated to reflux for 15minutes. The mixture was cooled to 5° C. to give a solid which wascollected by filtration, rinsed with ethyl acetate, and air dried togive the title compound.

PREPARATION 4 Synthesis of N,N-bis(2-chloroethyl)-N-benzylaminehydrochloride

Thionyl chloride (25.4 g, 130 mmol) and chloroform (20 mL) are combined.A solution of N,N-bis(2-hydroxyethyl)-N-benzylamine (25.4 g, 130 mmol)in chloroform (20 mL) is added dropwise over 1 hour. When the additionis complete the reaction mixture is refluxed for 1 hour. The reactionmixture is cooled to ambient temperature and diethyl ether was added toform a solid which is collected by filtration, rinsed with diethylether, and dried to give the title compound.

EXAMPLE 74 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide

74.1 Synthesis of 1-benzyl-4-(4-fluoro-phenyl)-4-cyano-piperidinehydrochloride

4-Fluorophenyl-acetonitrile (5.89 g, 40 mmol), and aqueous sodiumhydroxide solution (60 mL, 50% by weight) are combined and thenN,N-Bis(2-chloroethyl)-N-benzylamine hydrochloride (11.28 g, 42 mmol)and hexadecyltriethyl phosphonium bromide (1.02 g, 2 mmol) were added.The reaction mixture was heated to 100° C. and stirred vigorously for 1hour. The reaction mixture is cooled to ambient temperature and waterwas added. The diluted reaction mixture was acidified with 6Mhydrochloric acid solution and extracted with diethyl ether. The aqueouslayer is then made basic with solid potassium hydroxide and extractedwith ethyl acetate. The organic layer was separated, dried over MgSO₄,filtered, and evaporated in vacuo to give a residue. The residue wasadded to a solution of hydrochloric acid in methanol and the solutionwas evaporated in vacuo to give a solid. The solid was recrystallizedfrom methanol/ethyl acetate to the title compound: mp=263-264.

Analysis: calculated for C₁₉ H₁₉ FN₂. HCl C 68.98; H 6.09; N 8.47; FoundC 68.79; H 6.12; N 8.40.

74.2 Synthesis of 1-benzyl-4-(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide N-oxide

1-Benzyl-4-(4-fluoro-phenyl)-4-cyano-piperidine hydrochloride (7.8 g,26.5 mmol) was combined with aqueous sodium hydroxide (1.2 mL, 50% byweight) and ethanol (130 mL) and the mixture was heated to 50° C. Theheating was removed, and a solution of hydrogen peroxide (12.11 mL, 30%by weight in water, 106 mmol) was added at such a rate that thetemperature of the reaction mixture does not rise above 50° C. Thereaction mixture was then stirred at 50° C. for 4 hours. The reactionmixture was diluted with water (100 mL) and most of the solvent wasremoved in vacuo before adding water (200 mL) to form a solid which wascollected by filtration, rinsed with water, and dried in vacuo to givethe title compound.

74.3 Synthesis of 4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid amidehydrochloride

1-Benzyl-4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid amide N-oxide(5.3 g, 16.3 mmol) and 10% palladium-on-carbon (0.6 g) and acetic acid(100 mL) were combined in a pressure vessel. The reaction mixture wastreated with hydrogen on a Parr apparatus at an initial pressure of 53psi of hydrogen. When hydrogen consumption stopped the catalyst wasremoved by filtration. The filtrate was evaporated in vacuo to give aresidue. The residue was dissolved in ethyl acetate (150 mL), acidifiedby the addition of 12M aqueous hydrochloric acid solution (5 mL), andheated to reflux for 10 minutes. The mixture was cooled to ambienttemperature to give a solid which was collected by filtration, rinsedwith ethyl acetate, recrystallized from methanol/ethyl acetate to givethe title compound.

74.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-fluoro-phenyl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(1.65 g, 3.1 mmol) and 4-(4-fluoro-phenyl)-piperidine-4-carboxylic acidamide hydrochloride (1.1 g, 4.25 mmol) to give the title compound: R_(f)=0.27 (silica gel, 10% methanol/chloroform).

EXAMPLE 75 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(3-methoxy-phenyl)-piperidine-4-carboxylicacid amide

75.1 Synthesis of 1-benzyl-4-(3-methoxy-phenyl)-4-cyano-piperidinehydrochloride

Prepare by the method of example 74.1 using 3-methoxyphenyl-acetonitrile(3.68 g, 25 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride(7.05 g, 26.25 mmol) to the title compound.

75.2 Synthesis of 1-benzyl-4-(3-methoxy-phenyl)-piperidine-4-carboxylicacid amide N-oxide

Prepare by the method of example 74.2 using1-benzyl-4-(3-methoxy-phenyl)-4-cyano-piperidine hydrochloride (2.5 g,8.16 mmol) to give the title compound.

75.3 Synthesis of 4-(3-methoxy-phenyl)-piperidine-4-carboxylic acidamide hydrochloride

Prepare by the method of example 74.3 using1-benzyl-4-(3-methoxy-phenyl)-piperidine-4-carboxylic acid amide N-oxide(2.5 g, 16. mmol) to give the title compound.

75.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(3-methoxy-phenyl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.75 g, 1.4 mmol) and 4-(3-methoxy-phenyl)-piperidine-4-carboxylic acidamide hydrochloride (0.5 g, 1.85 mmol) to give the title compound: R_(f)=0.43 (silica gel, 10% methanol/chloroform).

EXAMPLE 76 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide

76.1 Synthesis of 1-benzyl-4-(4-methyl-phenyl)-4-cyano-piperidine

4-Methylphenyl-acetonitrile (1.66 g, 12.6 mmol), sodium iodide (0.25 g),and sodium hydride (50.4 mmol) were combined in dimethylformamide (50mL) and stirred until gas evolution ceases. A solution ofN,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (2.8 g, 12.6 mmol) indimethylformamide (50 mL) was added dropwise. After 24 hours, thereaction mixture was heated to 70° C. and stirred for 2 days. Thesolvent was removed by evaporation in vacuo to give a residue and theresidue was partitioned between water and dichloromethane. The organiclayer was separated, dried over MgSO₄, filtered and evaporated in vacuoto give a residue which was chromatographed on silica gel eluding with2/1 hexane/ethyl acetate to give the title compound.

76.2 Synthesis of 1-benzyl-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide N-oxide

Prepare by the method of example 74.2 using1-benzyl-4-(4-methyl-phenyl)-4-cyano-piperidine (5 mmol) to give thetitle compound.

76.2 Synthesis of 4-(4-methyl-phenyl)-piperidine-4-carboxylic acid amidehydrochloride

Prepare by the method of example 74.3 using1-benzyl-4-(4-methyl-phenyl)-piperidine-4-carboxylic acid amide N-oxide(5 mmol) to give the title compound.

76.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-methyl-phenyl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.75 g, 1.4 mmol) and 4-(methyl-phenyl)-piperidine-4-carboxylic acidamide hydrochloride (1.85 mmol) to give the title compound.

EXAMPLE 77 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide

77.1 Synthesis of 1-benzyl-4-(4-chloro-phenyl)-4-cyano-piperidine

Prepare by the method of example 76.1 using 4-chlorophenyl-acetonitrile(1.0 g, 6.6 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride(1.5 g, 6.6 mmol) to give the title compound.

77.2 Synthesis of 1-benzyl-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide N-oxide

Prepare by the method of example 74.2 using1-benzyl-4-(4-chloro-phenyl)-4-cyano-piperidine (5 mmol) to give thetitle compound.

77.3 Synthesis of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid amidehydrochloride

A mixture of 1/9 by volume of formic acid/methanol (50 mL) was carefullyadded to platinum black (2.2 g). A solution of1-benzyl-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid amide N-oxide(2.6 g) in methanol (10 mL) was added. After 18 hours, the reactionmixture was filtered through a bed of celite and the filtrate wasevaporated in vacuo to give a residue. The residue was dissolved inethyl acetate (10 mL) and a 1M solution of hydrochloric acid in methanol(4 mL) added. The reaction mixture was evaporated in vacuo to give aresidue which was dissolved in methanol and treated with diethyl etherto give a solid. The solid was collected by filtration and dried to givethe title compound.

77.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.75 g, 1.4 mmol) and 4-(chloro-phenyl)-piperidine-4-carboxylic acidamide hydrochloride (1.85 mmol) to give the title compound.

EXAMPLE 78 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide

78.1 Synthesis of1-benzyl-4-(4-trifluoromethyl-phenyl)-4-cyano-piperidine

Prepare by the method of example 76.1 using4-trifluoromethylphenyl-acetonitrile (1.5 g, 8.1 mmol) andN,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (1.9 g, 8.1 mmol) togive the title compound.

78.2 Synthesis of1-benzyl-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid amideN-oxide

Prepare by the method of example 74.2 using1-benzyl-4-(4-trifluoromethyl-phenyl)-4-cyano-piperidine (5 mmol) togive the title compound.

78.3 Synthesis of 4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide hydrochloride

Prepare by the method of example 77.3 using1-benzyl-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid amideN-oxide (4 mmol) to give the title compound.

78.4 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(4-trifluoromethyl-phenyl)-piperidine-4-carboxylicacid amide

Prepare by the method of example 27.3.1 using2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate(0.75 g, 1.4 mmol) and4-(trifluoromethyl-phenyl)-piperidine-4-carboxylic acid amidehydrochloride (1.85 mmol) to give the title compound.

EXAMPLE 79 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-difluoromethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

79.1 Synthesis of methyl 3,5-dimethoxy-4-difluoromethoxy-benzoate

Sodium hydride (0.144 g, 6 mmol) was added portionwise to a solution ofmethyl 3,5-dimethoxy-4-hydroxy-benzoate (0.21 g, 1 mmol) intetrahydrofuran (20 mL) cooled to 0° C. After 2 hours,chlorodifluoromethane (gas) was introduced by sparge for 10 minutesevery 2 hours (5 times). After 18 hours, an additional portion of sodiumhydride (0.048 g, 2 mmol) was added followed by chlorodifluoromethane(gas) sparge for 10 minutes. The reaction mixture was sealed and stirredfor 3 weeks. The reaction mixture was cooled to -78° C. and methanol (5mL) was added. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, dried over MgSO₄,filtered, and evaporated in vacuo to give the title compound.

79.2 Synthesis of 3,5-dimethoxy-4-difluoromethoxy-benzoic acid

Methyl 3,5-dimethoxy-4-difluoromethoxy-benzoate (92.8 mg, 0.35 mmol) wascombined with 1M sodium hydroxide solution (20 mL) and methanol (10 mL).After 4 hours, the reaction was acidified with 1M hydrochloric acidsolution and extracted with ethyl acetate. The organic layer was driedover MgSO₄, filtered, and evaporated in vacuo to give the titlecompound: R_(f) =0.48 (silica gel, 10% methanol/dichloromethane).

79.3 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-difluoromethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using3,5-dimethoxy-4-difluoromethoxy-benzoic acid (85 mg, 0.34 mmol) and1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (241 mg, 0.5 mmol). Purify be chromatography onsilica gel eluting sequentially with 50% ethyl acetate/hexane and then6% methanol/dichloromethane to give the title compound:

R_(f) =0.48 (silica gel, 10% methanol/dichloromethane).

EXAMPLE 80 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

80.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Prepare by the method of example 70.5 using3,5-dimethoxy-4-hydroxy-benzoic acid (99 mg, 0.5 mmol) and1-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride (241 mg, 0.5 mmol). Purify be chromatography onsilica gel eluting sequentially with 50% ethyl acetate/hexane and then6% methanol/dichloromethane to give the title compound: R_(f) =0.38(silica gel, 10% methanol/dichloromethane).

EXAMPLE 81 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(2-diethylamino-ethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

81.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-(2-diethylamino-ethyl)-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide

Combine1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (1 mmol) and sodium hydride (2 mmol) in tetrahydrofuran (10mL). Add diethylaminoethylchloride hydrochloride (1 mmol). After 24hours, partition the the reaction mixture between water and ethylacetate. Separate the organic layer, dry over MgSO₄, filter, andevaporate in vacuo to give the title compound.

EXAMPLE 82 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide

82.1 Synthesis of1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide

Combine1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide (1.0 mmol) and dichloromethane (10 mL). Cool to 0° C. Addportionwise, m-chloroperbenzoic acid (1.0 mmol). After the addition iscomplete, warm to ambient temperature. After 18 hours, extract thereaction mixture with water. Separate the organic layer, dry over MgSO₄,filter, and evaporate in vacuo to give a residue. Purify the residue bychromatography to give the title compound.

The compounds of the present invention are useful in theirpharmacological activities such as tachykinin antagonism, especiallysubstance P and neurokinin A antagonism, and the like. One object of thepresent invention is to provide new and useful antagonists oftachykinins, especially substance P and neurokinin A. A particularobject of the present invention are those compounds that exhibit bothNK₁ and NK₂ receptor antagonism. For some compounds, significantantagonism of NK₃ receptors may additionally be useful.

The compounds of the present invention are believed to exert theirtherapeutic effect through antagonism of NK₁ and NK₂ receptors andthereby provide relief for diseases and conditions associated withinflammation, pain, and the central nervous system. However, it isunderstood that the present invention is not limited by any particulartheory or proposed mechanism to explain its effectiveness in an end-useapplication.

A further object of the present invention is to provide compounds,stereoisomers, or pharmaceutically acceptable salts thereof, for thetreatment and prevention of various diseases in a patient in needthereof. Because the compounds of the present invention are tachykininantagonists, they are potentially useful in the treatment of conditionsassociated with inflammation, including asthma, allergies, bronchitis,rhinitis, Crohn's disease, ulcerative colitis, rheumatoid arthritis,osteoarthritis, migraine, cystitis and hypersensitivity reactions.Tachykinin antagonism may also be appropriate therapy for the treatmentof cough, emesis, pain, peripheral neuropathy, post-herpetic neuralgia,adverse immunological reactions, blood flow disorders due tovasodilation, ophthalmic diseases, such as conjuctivitis and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria andthe like. Various central nervous system disorders including anxiety,depression, psychosis, schizophrenia and dementia may also be amenableto treatment with tachykinin antagonists.

The compounds of formula (1) are believed to exert their inhibitoryeffect through antagonism of NK₁ and NK₂ receptors and thereby providerelief for neurogenic inflammatory diseases including but not limited toasthma and other inflammatory conditions of the lung. Additionally,compounds of the present invention are also believed to be useful forconditions associated with rhinitis, cough, and pain.

Various diseases and conditions described to be treated herein, are wellknown and appreciated by those skilled in the art. It is also recognizedthat one skilled in the art may affect the associated diseases andconditions by treating a patient presently afflicted with the diseasesor conditions or by prophylactically treating a patient afflicted withthe diseases or conditions with a therapeutically effective amount ofthe compounds of formula (1).

As used herein, the term "patient" refers to a warm blooded animal suchas a mammal which is afflicted With a particular inflammatory diseasestate. It is understood that guinea pigs, dogs, cats, rats, mice,horses, cattle, sheep, and humans are examples of animals within thescope of the meaning of the term.

As used herein, the term "therapeutically effective amount" of acompound of formula (1) refers to an amount which is effective incontrolling diseases and conditions associated with inflammation, pain,and the central nervous system. The term "controlling" is intended torefer to all processes wherein there may be a slowing, interrupting,arresting, or stopping of the progression of the diseases and conditionsdescribed herein, but does not necessarily indicate a total eliminationof all disease and condition symptoms, but does include prophylactictreatment of the diseases and conditions associated with inflammation,pain, and the central nervous system.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, the dose, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the specific disease involved; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

A therapeutically effective amount of a compound of formula (1) isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are ableto be determined by one skilled in the art.

In effecting treatment of a patient afflicted with the diseases andconditions described above, a compound of formula (1) can beadministered in any form or mode which makes the compound bioavailablein a therapeutically effective amount, including oral, inhalation, andparenteral routes. For example, compounds of formula (1) can beadministered orally, by inhalation of an aerosol or dry powder,subcutaneously, intramuscularly, intravenously, transdermally,intranasally, rectally, topically, and the like. Oral or inhalationadministration is generally preferred for treatment of respiratorydiseases, e.g. asthma. One skilled in the art of preparing formulationscan readily select the proper form and mode of administration dependingupon the particular characteristics of the compound selected, thedisease or condition state to be treated, the stage of the disease orcondition, and other relevant circumstances. (Remington's PharmaceuticalSciences, 18th Edition, Mack Publishing Co. (1990)).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts,such as acid addition salts or base addition salts, for purposes ofstability, convenience of crystallization, increased solubility and thelike.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (1) in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solution, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the compound of the presentinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention may be determined bysomeone skilled in the art.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the compound of formula (1)present in such compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations are able to bedetermined by one skilled in the art.

The compounds of the present invention may also be administered byinhalation, such as by aerosol or dry powder. Delivery may be by aliquefied or compressed gas or by a suitable pump system which dispensesthe the compounds of the present invention or a formulation thereof.Formulations for administration by inhalation of compounds of formula(1) may be delivered in single phase, bi-phasic, or tri-phasic systems.A variety of systems are available for the administration by aerosols ofthe compounds of formula (1). Dry powder formulations are prepared byeither pelletizing or milling the compound of formula (1) to a suitableparticle size or by admixing the pelletized or milled compound offormula (1) with a suitable carrier material, such as lactose and thelike. Delivery by inhalation includes the necessary container,activators, valves, subcontainers, and the like. Preferred aerosols anddry powder formulations for administration by inhalation can bedetermined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols, beewax, mineral oil, diluents such as water and alcohol, and emulsifiersand stabilizers. Topical formulations may contain a concentration of theformula (1) or its pharmaceutical salt from about 0.1 to about 10% w/v(weight per unit volume).

The solutions or suspensions may also include one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

EXAMPLE 14 Antagonism of Iodinated Tachykinin Binding to NK₁ and NK₂Receptors by Putative Antagonists

The NK₁ receptor affinity of proposed tachykinin antagonists wasevaluated in guinea pig lungs (Keystone Biologicals, Cleveland, Ohio),affinity for the NK₂ receptor evaluated in HSKR-1 cells (which are mouse3T3 fibroblasts expressing the human jejunal NK₂ receptor) and NK-3receptor affinity was evaluated in freshly collected guinea pig cerebralcortex. Tissues or cells were homogenized with a Polytron in 15 volumesof 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and centrifuged. The pellet wasresuspended in Tris-HCl buffer and was centrifuged; the pellet waswashed twice by resuspension. The final pellet was resuspended at aconcentration of 40 mg/ml for tissues (guinea pig lung and cerebralcortex) and 20 mg/ml for cells in incubation buffer and remained at roomtemperature for at least 15 min prior to use. Receptor binding wasinitiated by addition of 250 ul membrane preparation in duplicate to 0.1nM of the following radioligands: ¹²⁵ I-Bolton Hunter Lys-3 labeledsubstance P; ¹²⁵ iodohistidyl-1-neurokinin A; and ¹²⁵ I-Bolton Hunterlabeled Lys-4 eledoisin in a final volume of 500 ul of buffer containing50 mM Tris-HCl (pH 7.4 at room temperature), 0.1% bovine serum albumin,2 mM MnCl₂, 40 ug/ml bacitracin, 4 μg/ml leupeptin and chymostatin, 1 μMthiorphan and various doses of the putative tachykinin antagonists.Incubations were performed at room temperature for 90 min (NK₁ receptorassays) or 2 hr (NK₂ and NK₃ receptor assays); binding was terminated byaddition of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and filtration undervacuum through GF/B filters presoaked with 0.1% polyethyleneimine (NK₁receptor assays) or 0.5% bovine serum albumin (NK₂ and NK₃ receptorassays). Filter bound radioactivity was quantitated in a gamma counter.Nonspecific binding was defined as binding in the presence of 1 μMsubstance P, neurokinin A, or eledoisin. Specific binding was calculatedby subtracting nonspecific binding from total binding. Competition ofiodinated SP, NKA, or eledoisin binding by test compounds or standardswas expressed as a percentage of this maximum competition. IC₅₀ values(concentration required to inhibit 50% of receptor binding) weregenerated for each of the test compounds by nonlinear regression usingan iterative curve fitting program (GraphPAD Inplot, San Diego, Calif.).

IC₅₀ values for the compounds in question are found in Table 2 andrepresent the mean of several experiments. Several of the compoundspresented, e.g. Example 3 exhibits high affinity for both NK₁, and NK₂receptors as well as for NK₃ receptors.

                                      TABLE 2                                     __________________________________________________________________________                                              NK-2 NK-1 NK-3                      EXAMPLE                                                                             STRUCTURE                           IC.sub.50 (nM)                                                                     IC.sub.50                                                                          IC.sub.50                 __________________________________________________________________________                                                        (nM)                       2                                                                                   ##STR31##                          34   131   65                       13                                                                                   ##STR32##                          14    74                             4                                                                                   ##STR33##                          74    48   41                        5                                                                                   ##STR34##                          41    20   65                        3                                                                                   ##STR35##                          15    5   --                         1                                                                                   ##STR36##                           7   270  162                       10                                                                                   ##STR37##                          11   255  1191                      11                                                                                   ##STR38##                          127  196  203                        9                                                                                   ##STR39##                          118   49  183                        6                                                                                   ##STR40##                          15   182  --                         7                                                                                   ##STR41##                          10   240  202                       12                                                                                   ##STR42##                          179  810  --                         8                                                                                   ##STR43##                          94   1480 --                        23                                                                                   ##STR44##                          2683 20.0 --                        21                                                                                   ##STR45##                          760  183  2304                      22A                                                                                  ##STR46##                          1187 17.4 --                        20                                                                                   ##STR47##                          8.40 4.65  21                       20A                                                                                  ##STR48##                          7.93 2.99 --                         3A                                                                                  ##STR49##                          21   5.97 54.2                       5A                                                                                  ##STR50##                          40   20   --                        __________________________________________________________________________

EXAMPLE 15 Antagonism of NK₁ and NK₂ Receptor MediatedPhosphatidylinositol Turnover

Tachykinin-mediated inositol phosphate accumulation was measured in UC11or SKLKB82#3 cells in the presence and absence of NK₁ or NK₂ receptorantagonists, respectively. Tissues were incubated in Krebs-Henseleitbuffer at 37° C. with 95% O₂ -5% CO₂ gassing. Tissues were thenincubated with fresh buffer containing 100 μCi of myo-[2-³ H(N)]inositol at 37° C. for 60 min with gentle gassing. After washing twicein 5 ml room temperature buffer containing 10 mM LiCl, tissues wereincubated for 30 min at room temperature with a buffer change at 15 min.Buffer was removed and Krebs-Henseleit buffer (containing 40 μg/mlbacitracin, 4 μg/ml each of leupeptin and chymostatin, 0.1% bovine serumalbumin and 10 mM each of thiorphan and LiCl) added. After 15 min, SPwas added to UC11 cells or NKA to SKLKB82#3 cells at variousconcentrations to start the reaction. After incubation for 60 min atroom temperature the reaction was terminated by addition of 930 μlchloroform:methanol (1:2 by volume) to each tube, followed by 310 μlchloroform and 310 μl doubly distilled water. Samples were vortexed,centrifuged, and 0.9 ml of the aqueous (top) phase removed and added to2 ml ddH₂ O. The mixture was vortexed and loaded onto a 50% Bio-Rad AG1-X8 (formate form, 100-200 mesh) exchange column (Bio-Rad Laboratories,Hercules, Calif.). The columns were washed, in order, with: 1) 10 mldoubly distilled water, 2) 5 ml of 5 mM disodium tetraborate/60 mMsodium formate, and 3) 5 ml of 1M ammonium formate/0.1M formic acid. Thethird elution was collected and 1 ml counted in 7 ml scintillationfluid. A 50 μl aliquot of the organic (bottom) phase was removed, driedin a scintillation vial and counted in 7 ml scintillation fluid.

The ratio of DPM in the aqueous phase aliquot (total inositolphosphates) to the DPM in the 50 μl organic phase aliquot (total [³H]-inositol incorporated) was calculated for each sample. Data areexpressed as a percent of agonist-induced accumulation of [³ H]-inositolphosphates over basal levels. The ratios in the presence of testcompound and/or standards were compared to the ratios for controlsamples (i.e. no stimulating agonist). Dose-response graphs wereconstructed and the abilities of the test compounds to inhibittachykinin-induced phosphatidyinositol turnover determined with the aidof a computer program. FIG. 1 illustrates the ability of Example 3 toproduce dose related antagonism of the receptor mediated SP or NKAinduced PI turnover in UC11 (FIG. 1a) or SKLKB82#3 cells (FIG. 1b),respectively. Data is expressed as percent stimulation of total inositolphosphate accumulation over basal levels and normalized to the maximumresponse produced by SP. These data suggest Example 3 has no agonistactivity and antagonizes both NK₁ (on UC11 cells) and NK₂ (on SKLKB82#3)receptors in a dose-dependent manner. Schild analysis is performed usingdose response curves (such as those presented in FIGS. 1a and 1b) toobtain a value indicative of the Strength of a competitive antagonistand is expressed as the pA₂, which is the negative logarithm of themolar concentration of antagonist which reduces the effect of a dose ofagonist to one-half of that expected at the dose of agonist. Table 3contains data demonstrating the ability of the compounds of Example 3A;Example 5A; and Example 20 to functionally antagonize the effects of SPor NKA in vitro. These compounds antagonized both NK₁ and NK₂ receptorsby nearly equivalent amounts. It is further important to note that noneof the compounds alone stimulated PI turnover suggesting an absence ofagonist activity.

                  TABLE 3                                                         ______________________________________                                        Apparent Affinities of Compounds for Tachykinin Receptors                            NK-1 RECEPTOR NK-2 RECEPTOR                                            COMPOUND pA.sub.2  -SLOPE    pA.sub.2                                                                              -SLOPE                                   ______________________________________                                        EXAMPLE 3A                                                                             7.91      0.90      8.75    0.73                                              (7.71-8.23)                                                                             (0.65-1.15)                                                                             (7.78-9.72)                                                                           (0.49-0.97)                              EXAMPLE 5A                                                                             7.32      1.17      7.35    1.11                                              (4.84-9.80)                                                                             (0.41-1.93)                                                                             (6.93-7.77)                                                                           (0.99-1.23)                              EXAMPLE 20                                                                             8.19      1.03      8.67    1.00                                              (7.37-9.00)                                                                             (0.78-1.28)                                                                             (8.20-9.14)                                                                           (0.63-1.37)                              ______________________________________                                         Values are mean (95% confidence limits) derived from Schild analysis of       2-3 experiments per compound per receptor.                               

EXAMPLE 16 Antagonism of SP-Induced Plasma Protein Extravasation inGuinea Pig Trachea

SP-induced protein leakage through postcapillary venules was assessed bymeasuring Evans Blue dye accumulation in guinea pig trachea. Animalswere anesthetized with pentobarbital then injected with Evans Blue dye(20 mg/kg, i.v., prepared in 0.9% NaCl solution). One minute after dyeadministration, the antagonist was administered (i.v.) followed by SP(0.3 nmole/kg, i.v.) and, after 5 min, excess dye removed from thecirculation by transcardiac perfusion with 50 ml 0.9% NaCl solution. Thetrachea and primary bronchi were removed, blotted dry and weighed. Dyequantitation was performed spectrophotometrically (620 nM) afterextracting tissues in formamide for 24 hr at 50° C. Values weresubtracted from background (dye only, no agonist). ED₅₀ (dose ofcompound which inhibits SP-induced plasma protein extravasation by 50%)was calculated from linear regression analysis.

FIG. 2 illustrates the ability of Example 3 to produce a dose relatedantagonism of SP-induced plasma protein extravasation in guinea pigtrachea. These data suggest that Example 3 acts as an antagonist of NK₁receptors in vivo.

Table 4, "Antagonism of SP-Induced Plasma Protein Extravasation inGuinea Pig Airways", contains data for the compound of Example 3 and its(+)-enantiomer the compound of Example 20A. These compounds areequipotent NK-1 receptor antagonists in this system.

                  TABLE 4                                                         ______________________________________                                        Antagonism of SP-induced Plasma                                               Protein Extravasation in Guinea Pig Trachea                                   COMPOUND      ED.sub.50 (mg/kg)                                               ______________________________________                                        Example 3A    0.17 (0.004-0.274)                                              Example 20A   0.20 (0.004-0.31)                                               ______________________________________                                         Values are mean (95% confidence limits). Compounds were injected              intravenously 2 min prior to SP administration. ED.sub.50 values are base     on at least 3 doses; at least 4 animals were used per dose.              

EXAMPLE 17 Antagonism of NKA and Capsaicin Induced Respiratory Effectsin Conscious Guinea Pigs

In vivo experiments were performed using male Duncan Hartley guinea pigs(250-350 g). Changes in conscious breathing patterns were monitored infour animals simultaneously using modified whole body plethysmographyconsisting of four small plexiglass boxes each connected to a referencebox via Validyne DP 45-16 differential pressure transducers. The 4 boxeswere equipped with an air supply line (also used for aerosol delivery)and an exhaust air line. Supply and exhaust lines were of the samelength and narrow bore and arose from a common supply chamber and ventedto a common exhaust chamber. This system was used to ensure thatfluctuations in supply air and atmospheric pressure would remain inphase and be eliminated from the net signal by the differential pressuretransducers. The analog pressure signals were digitalized via a DataTranslation DT2821 A to D board. Data were collected at a rate of 100samples/second/animal. Each cycle of pressure change was analyzed usingthe following parameters: rising and falling slope determined betweenminimum and maximum pressures, the ratio of rising over falling slope,and the magnitude of the change between initial trough pressure and peakcycle pressure. Using these values (and observing the animals) thepressure cycles were characterized into normal breaths, forcedexhalations (apparent by abdominal heaving), significant respiratoryevents (SREs; usually coughs, less often sneezes or gasps which werecharacterized by transient, extremely large pressure increases whichwere distinguishable from noise) and movement/noise with a PCAT 286running a System V UNIX operating system. Dyspnea was defined as asignificant, sustained increase in plethysmograph pressure which wasassociated with an observable shift to labored breathing in the animal.

During the course of a typical experiment in which airway responsivenessto various bronchoconstricting agents was examined, aerosols weredelivered for 19 min (0.33 ml/min) using a DeVilbiss Ultraneb 99ultrasonic nebulizer and animals monitored during this time. Prior tonebulization, 1 min of resting breathing was collected to establish abaseline pressure. In preliminary experiments, various concentrations ofthe bronchoconstrictive agents were evaluated and the concentrationchosen which maximized the number of animals exhibiting dyspnea butminimized the severity of the response. Hence, neurokinin A wasdelivered at a final concentration of 0.05%, and capsaicin, 0.001%. Thevehicle for nebulization of all bronchoconstrictive agents was phosphatebuffered saline (pH 7.4) which elicited no respiratory effects itself.Putative tachykinin antagonists were administered either (i.v.) 20 minprior to onset of aerosol exposure or orally 1 hour prior to onset (toguinea pigs after an overnight fast).

"Antagonism of NKA-Induced Respiratory Effects in Conscious Guinea Pigs"

Table 6 illustrates the effects of the compounds of Example 3; Example20A; and Example 5A on respiratory effects induced by NKA aerosol. Allcompounds reduced the effects of NKA aerosol as suggested by a decreasein the number of animals exhibiting dyspnea in response to thetachykinin or an increase in the period of time (or amount of aerosol)required to elicit the dyspnea response. These effects were dosedependent i.e. the higher the dose of compound, the greater attenuationof NKA-mediated effects. These data indicate that these compounds arecapable of producing NK₂ receptor antagonism in guinea pigs in vivo.

                  TABLE 6                                                         ______________________________________                                        Modulation of Respiratory Effects Produced by NKA Aerosol                     in Conscious Guinea Pigs                                                      TREATMENT DYSPNEA INCIDENCE                                                                             DYSPNEA ONSET (sec)                                 ______________________________________                                        VEHICLE   100% (37/37)     397 ± 29.5                                      Example 3                                                                      5 mg/kg  86% (6/7)       394 ± 32                                         10 mg/kg  60% (6/10)       801 ± 104                                       Example 20A                                                                    1 mg/kg  100% (10/10)    451 ± 30                                          5 mg/kg  90% (9/10)      706 ± 82                                         10 mg/kg  70% (7/10)       829 ± 105                                       Example 5A                                                                     5 mg/kg  60% (3/5)       654 ± 37                                         10 mg/kg  54% (7/13)      608 ± 65                                         ______________________________________                                         Compounds were administered 20 min prior to initiation of NKA aerosol         (0.05%). Values for each treatment represent the mean and SEM of data fro     5-37 animals per dose.                                                   

Capsaicin aerosol is known to promote release of the tachykinins SP andNKA from sensory nerves in the airways of guinea pigs which may then actupon NK₁ and NK₂ receptors, respectively to elicit respiratory effects.The ability of the compounds of Example 3A; and Example 20A to attenuatecapsaicin-induced respiratory effects, shown in Table 7a, is inferredfrom their ability to reduce incidence of dyspnea, prolong the onset ofthe response and reduce the number of coughs/gasps which occur duringaerosol exposure. The compound of Example 3A as well as the compound ofExample 5 also antagonize the effects of capsaicin aerosol whenadministered orally as shown in Table 7b. These data suggest that thecompounds of Example 3A; Example 20A; and Example 5 inhibit theendogenous tachykinins released by capsaicin aerosol which producerespiratory alterations in conscious guinea pigs in vivo.

                  TABLE 7a                                                        ______________________________________                                        Modulation of Respiratory Effects Produced by Capsaicin                       Aerosol in Conscious Guinea Pigs: Intravenous                                 Administration of Putative Tachykinin Antagonists                                                          MAXIMUM                                                             DYSPNEA   PRESSURE                                         TREAT- DYSPNEA     ONSET     INCREASE                                                                              SRE                                      MENT   INCIDENCE   (sec)     (mmH.sub.2 O)                                                                         NUMBER*                                  ______________________________________                                        Vehicle                                                                              100%    (60/60)   286 ± 14.3                                                                       1.09 ± 0.05                                                                        10.4 ± 0.88                         Example                                                                       3A                                                                             10 mg/kg                                                                            89%     (7/8)   480 ± 80                                                                           0.83 ± 0.18                                                                        8.50 ± 1.9                          Example                                                                       20A                                                                             1 mg/kg                                                                            77.8%   (7/9)   331 ± 22                                                                           1.0 ± 0.1                                                                          9.9 ± 2.7                           2.5 mg/kg                                                                            100%    (10/10) 426 ± 57                                                                           0.6 ± 0.1                                                                          8.3 ± 1.6                             5 mg/kg                                                                            44.4%   (4/9)    597 ± 186                                                                          0.8 ± 0.06                                                                        4.4 ± 1.9                            10 mg/kg                                                                            55.6%   (5/9)   592 ± 71                                                                           0.8 ± 0.1                                                                          3.3 ± 1.1                           ______________________________________                                         Values are mean and SEM of data derived from number of animals indicated      in parenthesis. Putative tachykinin antagonists were administered             intravenously 20 min prior to initiation of capsaicin aerosol (0.001%).       *SRE number indicates the number of coughs/gasps which occurred during th     19 min capsaicin exposure period.                                        

                  TABLE 7b                                                        ______________________________________                                        Modulation of Respiratory Effects Produced by Capsaicin                       Aerosol in Conscious Guinea Pigs: Oral Administration of                      Putative Tachykinin Antagonists                                                                            MAXIMUM                                                             DYSPNEA   PRESSURE                                         TREAT- DYSPNEA     ONSET     INCREASE                                                                              SRE                                      MENT   INCIDENCE   (sec)     (mmH.sub.2 O)                                                                         NUMBER*                                  ______________________________________                                        Vehicle                                                                              100%    (28/28) 335 ± 32                                                                           0.8 ± 0.0                                                                          7.9 ± 1.1                           Example                                                                       3A                                                                             25 mg/kg                                                                            80%     (8/10)  424 ± 120                                                                          0.7 ± 0.2                                                                          4.6 ± 1.0                            50 mg/kg                                                                            70%     (7/10)  434 ± 152                                                                          0.4 ± 0.1                                                                          2.8 ± 0.8                           100 mg/kg                                                                            50%     (5/10)  360 ± 120                                                                          0.4 ± 0.1                                                                          2.1 ± 0.5                           Example                                                                        25 mg/kg                                                                            66.7%   (6/9)   253 ± 47                                                                           0.7 ± 0.1                                                                          4.4 ± 1.2                            50 mg/kg                                                                            85.7%   (6/7)   384 ± 85                                                                           0.5 ± 0.1                                                                          4.9 ± 1.9                           ______________________________________                                         Values are mean and SEM of data derived from number of animals indicated      in parenthesis. Putative tachykinin antagonists were administered by oral     gavage 1 hr prior to initiation of capsaicin aerosol (0.001%). *SRE numbe     indicates the number of coughs/gasps which occurred during the 19 min         capsaicin exposure period.                                               

What is claimed is:
 1. A method for treating cough in a patient in needthereof comprising administering to said patient a therapeuticallyeffective amount of a compound of the formula ##STR51## wherein G₁ is--CH₂ -- or --C(O)--;G₂ is --CH₂ -- or --C(O)--; m is 2 or 3; n is 0 or1; Ar₁ is a radical chosen from the group: ##STR52## wherein R₁ is from1 to 3 substituents each independently chosen from the group consistingof hydrogen, halogen, hydroxy, CF₃, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; R₂is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; Ar₂ isa radical chosen from the group ##STR53## wherein R₃ is from 1 to 3substituents each independently chosen from the group consisting ofhydrogen, halogen, C₁ -C₆ alkoxy, hydroxy, --O--C(O)O--CH₂ --CH₃,--OC(O)CH₃, --CF₂ H, --(CH₂)_(q) NR₆ R₇, and --(CH₂)_(q) NR₈ R₉ whereinq is 2 or 3, R₆ is C₁ -C₆ alkyl, R₇ is C₁ -C₆ alkyl, R₈ and R₉ takentogether with the bonded nitrogen form a morpholine ring, piperidinering, 4-methylpiperazine ring, or pyrrolidine ring; R₄ is from 1 to 2substituents each independently chosen from the group consisting ofhydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; Y₁ is --C(O)NHR₅,--C(O)NR₆ R₇, or --C(O)NR₈ R₉ wherein R₅ is chosen from the groupconsisting of hydrogen, 3-hydroxy-2-butyryl-C₁ -C₆ alkyl ester,2-glutaryl-C₁ -C₆ alkyl ester, --(CH₂)_(q) NR₆ R₇, and --(CH₂)_(q) NR₈R₉ ; q is 2 or 3; R₆ is C₁ -C₆ alkyl; R₇ is C₁ -C₆ alkyl; R₈ and R₉taken together with the bonded nitrogen form a morpholine ring,piperidine ring, 4-methylpiperazine ring, or pyrrolidine ring; Y₂ is aradical chosen from the group ##STR54## wherein R₁₀ is from 1 to 3substituents each independently chosen from the group consisting ofhydrogen, halogen, CF₃, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; R₁₁ is from 1to 2 substituents each independently chosen from the group consisting ofhydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; or stereoisomers, oran N-oxide, or a pharmaceutically acceptable salt thereof.
 2. A methodof claim 1 wherein m is
 2. 3. A method of claim 1 wherein G₁ is --CH₂ --and G₂ is --C(O)--.
 4. A method of claim 1 wherein G₁ is --C(O)-- and G₂is --CH₂ --.
 5. A method of claim 1 wherein the compound is(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide.
 6. A method of claim 1 wherein the compound is(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide.
 7. A method of claim 1 wherein the compound is (+)- or(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid 4-methylpiperazine-amide or a mixture thereof.
 8. A method of claim1 wherein the compound is (+)- or(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid morpholine-amide or a mixture thereof.
 9. A method of claim 1wherein the compound is(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide hydrochloride.
 10. A method of claim 1 wherein the compoundis(+)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide citrate.
 11. A method of claim 1 wherein the compound is (+)-or(-)-1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylicacid amide N-oxide or a mixture thereof.
 12. A method for treating coughin a patient in need thereof comprising administering to said patient atherapeutically effective amount of a compound of the formula ##STR55##wherein G₁ is --CH₂ -- or --C(O)--;G₂ is --CH₂ -- or --C(O)--; m is 2 or3; n is 0 or 1; Ar₁ is a radical chosen from the group: ##STR56##wherein R₁ is from 1 to 3 substituents each independently chosen fromthe group consisting of hydrogen, halogen, hydroxy, CF₃, C₁ -C₆ alkyl,and C₁ -C₆ alkoxy; R₂ is from 1 to 2 substituents each independentlychosen from the group consisting of hydrogen, halogen, C₁ -C₆ alkyl, andC₁ -C₆ alkoxy; Ar₂ is a radical chosen from the group ##STR57## whereinR₃ is from 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkoxy, hydroxy, --O--C(O)O--CH₂--CH₃, --OC(O)CH₃, --CF₂ H, --(CH₂)_(q) NR₆ R₇, and --(CH₂)_(q) NR₈ R₉wherein q is 2 or 3, R₆ is C₁ -C₆ alkyl, R₇ is C₁ -C₆ alkyl, R₈ and R₉taken together with the bonded nitrogen form a morpholine ring,piperidine ring, 4-methylpiperazine ring, or pyrrolidine ring; R₄ isfrom 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; Y₁ andY₂ together with their attached carbon form a spirocyclic ring chosenfrom the group ##STR58## wherein R₁₂ is from 1 to 3 substituents eachindependently chosen from the group consisting of hydrogen, halogen,CF₃, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy; R₁₃ is hydrogen, C₁ -C₆ alkyl, orbenzyl;or stereoisomers, or an N-oxide, or a pharmaceutically acceptablesalt thereof.
 13. A method of claim 12 wherein m is
 2. 14. A method ofclaim 12 wherein G₁ is --CH₂ -- and G₂ is --C(O)--.
 15. A method ofclaim 12 wherein G₁ is --C(O)-- and G₂ is --CH₂ --.